Weight, mortality, years of healthy life, and active life expectancy in older adults. - Diehr, Paula; O'Meara, Ellen S; Fitzpatrick, Annette; Newman, Anne B; Kuller, Lewis; Burke, Gregory (J Am Geriatr Soc, 2008)
OBJECTIVES: To determine whether weight categories predict subsequent mortality and morbidity in older adults. DESIGN: Multistate life tables, using data from the Cardiovascular Health Study, a longitudinal population-based cohort of older adults. SETTING: Data were provided by community-dwelling seniors in four U.S. counties: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania. PARTICIPANTS: Five thousand eight hundred eighty-eight adults aged 65 and older at baseline. MEASUREMENTS: The age- and sex-specific probabilities of transition from one health state to another and from one weight category to another were estimated. From these probabilities, future life expectancy, years of healthy life, active life expectancy, and the number of years spent in each weight and health category after age 65 were estimated. RESULTS: Women who are healthy and of normal weight at age 65 have a life expectancy of 22.1 years. Of that, they spend, on average, 9.6 years as overweight or obese and 5.3 years in fair or poor health. For both men and women, being underweight at age 65 was associated with worse outcomes than being normal weight, whereas being overweight or obese was rarely associated with worse outcomes than being normal weight and was sometimes associated with significantly better outcomes. CONCLUSION: Similar to middle-aged populations, older adults are likely to be or to become overweight or obese, but higher weight is not associated with worse health in this age group. Thus, the number of older adults at a "healthy" weight may be much higher than currently believed.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Female; Health Status Indicators; Humans; Life Expectancy; Life Style; Male; Prognosis; Risk Factors; Sex Factors; Survival Rate; United States

Age, Alzheimer disease, and brain structure. - Raji, C A; Lopez, O L; Kuller, L H; Carmichael, O T; Becker, J T (Neurology, 2009)
BACKGROUND: Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo. OBJECTIVE: To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD. METHODS: A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race. RESULTS: With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex. CONCLUSION: Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Image Processing, Computer-Assisted; Linear Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Retrospective Studies

Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. - Sun, Cong; Klein, Ronald; Wong, Tien Y (Ophthalmology, 2009)
PURPOSE: To examine the associations of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and stroke in the Cardiovascular Health Study. DESIGN: Population-based prospective cohort study. PARTICIPANTS: A total of 1786 white and African-American participants free of CHD or 2228 participants free of stroke, aged 69 to 97 years. METHODS: AMD was evaluated from photographs taken in 1997 and 1998. MAIN OUTCOME MEASURES: Incident CHD and stroke ascertained using standardized methods. RESULTS: Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. Participants with early AMD (n = 277) had a higher cumulative incidence of CHD than participants without early AMD (25.8% vs. 18.9%, P = 0.001). By adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein, the presence of early AMD was associated with an increased risk of incident CHD (hazard ratio 1.57; 95% confidence interval, 1.17-2.22). Late AMD (n = 25) was not associated with incident CHD (hazard ratio 0.78; 95% confidence interval, 0.25-2.48). Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke. CONCLUSIONS: This study suggests persons with early AMD have a higher risk of CHD but not stroke in a population aged 69 to 97 years. This provides further support that AMD is associated with underlying systemic vascular disease.
Keywords: African Americans; Age Factors; Aged; Aged, 80 and over; Blood Pressure; Cholesterol, LDL; Coronary Disease; European Continental Ancestry Group; Female; Humans; Incidence; Macular Degeneration; Male; Prospective Studies; Risk Factors; Sex Factors; Stroke; Triglycerides; United States

Agreement between nosologist and cardiovascular health study review of deaths: implications of coding differences. - Ives, Diane G; Samuel, Paulraj; Psaty, Bruce M; Kuller, Lewis H (J Am Geriatr Soc, 2009)
OBJECTIVES: To compare nosologist coding of underlying cause of death according to the death certificate with adjudicated cause of death for subjects aged 65 and older in the Cardiovascular Health Study (CHS). DESIGN: Observational. SETTING: Four communities: Forsyth County, North Carolina (Wake Forest University); Sacramento County, California (University of California at Davis); Washington County, Maryland (Johns Hopkins University); and Pittsburgh, Pennsylvania (University of Pittsburgh). PARTICIPANTS: Men and women aged 65 and older participating in CHS, a longitudinal study of coronary heart disease and stroke, who died through June 2004. MEASUREMENTS: The CHS centrally adjudicated underlying cause of death for 3,194 fatal events from June 1989 to June 2004 using medical records, death certificates, proxy interviews, and autopsies, and results were compared with underlying cause of death assigned by a trained nosologist based on death certificate only. RESULTS: Comparison of 3,194 CHS versus nosologist underlying cause of death revealed moderate agreement except for cancer (kappa=0.91, 95% confidence interval (CI)=0.89-0.93). kappas varied according to category (coronary heart disease, kappa=0.61, 95% CI=0.58-0.64; stroke, kappa=0.59, 95% CI=0.54-0.64; chronic obstructive pulmonary disease, kappa=0.58, 95% CI=0.51-0.65; dementia, kappa=0.40, 95% CI=0.34-0.45; and pneumonia, kappa=0.35, 95% CI=0.29-0.42). Differences between CHS and nosologist coding of dementia were found especially in older ages in the sex and race categories. CHS attributed 340 (10.6%) deaths due to dementia, whereas nosologist coding attributed only 113 (3.5%) to dementia as the underlying cause. CONCLUSION: Studies that use only death certificates to determine cause of death may result in misclassification and potential bias. Changing trends in cause-specific mortality in older individuals may be a function of classification process rather than incidence and case fatality.
Keywords: Aged; Aged, 80 and over; Cause of Death; Coronary Disease; Death Certificates; Female; Forms and Records Control; Humans; Longitudinal Studies; Male; Stroke

Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. - Sink, Kaycee M; Leng, Xiaoyan; Williamson, Jeff; Kritchevsky, Stephen B; Yaffe, Kristine; Kuller, Lewis; Yasar, Sevil; Atkinson, Hal; Robbins, Mike; Psaty, Bruce; Goff, David C (Arch Intern Med, 2009)
BACKGROUND: Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control. METHODS: Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs). RESULTS: Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (-0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs. CONCLUSIONS: While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.
Keywords: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood-Brain Barrier; Cognition; Dementia; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Prospective Studies; Risk Factors

Association between elevated fibrosis markers and heart failure in the elderly: the cardiovascular health study. - Barasch, Eddy; Gottdiener, John S; Aurigemma, Gerard; Kitzman, Dalane W; Han, Jing; Kop, Willem J; Tracy, Russell P (Circ Heart Fail, 2009)
BACKGROUND: Myocardial fibrosis reflects excess collagen deposition in the extracellular left ventricular matrix, which has been associated with heart failure (HF). No studies have addressed the relation between fibrosis biomarkers and HF in the elderly. METHODS AND RESULTS: Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77+/-6 years, 48% women). Participants with systolic HF (n=131, left ventricular ejection fraction <55%) and those with diastolic HF (n=179, left ventricular ejection fraction > or =55%) were compared with controls (280 with cardiovascular risk factors, and 279 healthy individuals) using a nested case-control design. Fibrosis markers included carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III. Echocardiography was used to document systolic and diastolic function parameters. Analysis of variance and logistic regression analysis (per tertile odds ratios [OR]), adjusted by age, gender, race, hypertension, atrial fibrillation, coronary heart disease, baseline serum glucose, serum cystatin C, serum creatinine, C-reactive protein, any angiotensin-converting enzyme inhibitor, spironolactone or any diuretic, NT-proBNP, and total bone mineral density were performed. Systolic HF was associated with significantly elevated carboxyl-terminal telopeptide of collagen type I (OR=2.6; 95% CI=1.2 to 5.7) and amino-terminal peptide of procollagen type III (OR=3.3; 95% CI=1.6 to 5.8), when adjusting for covariates. Associations of diastolic HF were significant for carboxyl-terminal telopeptide of collagen type I (OR=3.9; 95% CI=1.9 to 8.3) and amino-terminal peptide of procollagen type III (OR=2.7; 95% CI=1.4 to 5.4). HF was not associated with elevated carboxyl-terminal peptide of procollagen type I (P>0.10), and fibrosis markers did not significantly differ between HF with diastolic versus those with systolic dysfunction (P>0.10) whereas NT-proBNP mean values were higher in systolic heart failure than in diastolic heart failure (P<0.0001). CONCLUSIONS: Fibrosis markers are significantly elevated in elderly individuals with diastolic or systolic HF. These associations remained significant when adjusting for covariates relevant to the aging process.
Keywords: Aged; Aged, 80 and over; Female; Fibrosis; Heart Failure; Humans; Male; Myocardium; Ultrasonography

Association of chronic kidney disease with the spectrum of ankle brachial index the CHS (Cardiovascular Health Study). - Ix, Joachim H; Katz, Ronit; de Boer, Ian H; Kestenbaum, Brian R; Allison, Matthew A; Siscovick, David S; Newman, Anne B; Sarnak, Mark J; Shlipak, Michael G; Criqui, Michael H (J Am Coll Cardiol, 2009)
OBJECTIVES: This study sought to determine the association of chronic kidney disease (CKD) with high ankle brachial index (ABI) measurement and to compare its strength with that of CKD with a low ABI. BACKGROUND: CKD is an important risk factor for cardiovascular disease (CVD) events. A high ABI, a marker of lower extremity arterial stiffness, is associated with CVD events and mortality. The association between CKD and high ABI is unknown. METHODS: The CHS (Cardiovascular Health Study) enrolled community-living people >65 years of age and measured kidney function and ABI. Glomerular filtration rate (GFR) was estimated using equations that incorporated either cystatin C or creatinine, and CKD was defined by estimated GFR <60 ml/min/1.73 m(2). The ABI was categorized as low (<0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (>1.40 or incompressible). Multinomial logistic regression was used to evaluate the associations of CKD with ABI categories. RESULTS: Among 4,513 participants, 23% had CKD, 13% had a low ABI, and 3% had a high ABI. In models adjusted for age, sex, race, hypertension, diabetes, smoking, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein, cystatin C-based CKD was associated with both low ABI (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.5; p <0.001) and high ABI (RR: 1.6; 95% CI: 1.0 to 2.3; p = 0.03). Results were similar when CKD was defined by creatinine. CONCLUSIONS: CKD is associated with both the high and the low extremes of ABI in community-living older people. Future studies should evaluate whether arterial stiffness is an important mechanism leading to CVD in people with CKD.
Keywords: Aged; Aged, 80 and over; Ankle Brachial Index; C-Reactive Protein; Cardiovascular Diseases; Chronic Disease; Cohort Studies; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Lipids; Male; Risk Factors

Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. - Pawlikowska, Ludmila; Hu, Donglei; Huntsman, Scott; Sung, Andrew; Chu, Catherine; Chen, Justin; Joyner, Alexander H; Schork, Nicholas J; Hsueh, Wen-Chi; Reiner, Alexander P; Psaty, Bruce M; Atzmon, Gil; et al. (Aging Cell, 2009)
The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
Keywords: Aged; Aged, 80 and over; Female; Follow-Up Studies; Forkhead Box Protein O3; Forkhead Transcription Factors; Genome, Human; Genotype; Humans; Insulin; Insulin-Like Growth Factor I; Longevity; Male; Osteoporosis; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-akt; Signal Transduction

Association of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study. - Carty, Cara L; Heagerty, Patrick; Heckbert, Susan R; Enquobahrie, Daniel A; Jarvik, Gail P; Davis, Scott; Tracy, Russell P; Reiner, Alexander P (J Atheroscler Thromb, 2009)
AIM: Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-alpha in influencing CVD was also explored. METHODS: SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during 14 years of follow-up. RESULTS: No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests. CONCLUSION: Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.
Keywords: Aged; Cardiovascular Diseases; Cholesterol, HDL; Cytokines; Female; Gene Regulatory Networks; Humans; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-6; Male; Polymorphism, Single Nucleotide; Proportional Hazards Models; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha; Tunica Intima

Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. - Dehghan, Abbas; Yang, Qiong; Peters, Annette; Basu, Saonli; Bis, Joshua C; Rudnicka, Alicja R; Kavousi, Maryam; Chen, Ming-Huei; Baumert, Jens; Lowe, Gordon D O; McKnight, Barbara; Tang, Weihong; et al. (Circ Cardiovasc Genet, 2009)
BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)). CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
Keywords: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Fibrinogen; Genetic Loci; Genome-Wide Association Study; Humans; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Young Adult

Association of renal function with cardiac calcifications in older adults: the cardiovascular health study. - Asselbergs, Folkert W; Mozaffarian, Dariush; Katz, Ronit; Kestenbaum, Bryan; Fried, Linda F; Gottdiener, John S; Shlipak, Michael G; Siscovick, David S (Nephrol Dial Transplant, 2009)
BACKGROUND: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly. METHODS: From the Cardiovascular Health Study, a community-based cohort of ambulatory adults >or= age 65, a total of 3929 individuals (mean +/- SD age 74 +/- 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C. RESULTS: The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m(2) (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m(2) was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16-2.06), P = 0.003] and not associated with AAC [1.30 (0.97-1.74), P = 0.085] and AVS [1.15 (0.86-1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05-1.21), P = 0.001] and not associated with AAC [1.07 (1.00-1.15), P = 0.054] and AVS [0.99 (0.93-1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m(2) and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m(2), increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05). CONCLUSIONS: In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m(2) and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m(2), increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.
Keywords: Aged; Aortic Valve; Calcinosis; Case-Control Studies; Cohort Studies; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Heart Valve Diseases; Humans; Kidney Diseases; Male; Mitral Valve; Risk Factors

Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. - Jenny, Nancy Swords; Arnold, Alice M; Kuller, Lewis H; Tracy, Russell P; Psaty, Bruce M (Arterioscler Thromb Vasc Biol, 2009)
OBJECTIVE: We examined associations of pentraxin 3 (PTX3), a vascular inflammation marker, with incident cardiovascular disease (CVD) and all-cause death. METHODS AND RESULTS: 1583 Cardiovascular Health Study participants free of prevalent CVD were included. Nonexclusive case groups were angina (n=476), myocardial infarction (MI; n=237), stroke (n=310), CVD death (n=282), and all-cause death (n=772). 535 participants had no events. PTX3 levels were higher in those with subclinical CVD (1.90+/-1.89 ng/mL) than those without (1.71+/-1.88 ng/mL; P=0.001). Using Cox regression adjusted for age, sex, and ethnicity, a standard deviation increase in PTX3 (1.89 ng/mL) was associated with CVD death (hazard ratio 1.11; 95% confidence interval 1.02 to 1.21) and all-cause death (1.08; 1.02 to 1.15). PTX3 was not associated with angina (1.09; 0.98 to 1.20), MI (0.96; 0.81 to 1.12), or stroke (1.06; 0.95 to 1.18). Adding C-reactive protein (CRP) or CVD risk factors to the models had no significant effects on associations. CONCLUSIONS: In these older adults, PTX3 was associated with CVD and all-cause death independent of CRP and CVD risk factors. PTX3 likely reflects different aspects of inflammation than CRP and may provide insight into vascular health in aging and chronic diseases of aging that lead to death.
Keywords: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Female; Health Surveys; Humans; Inflammation Mediators; Linear Models; Male; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Serum Amyloid P-Component; Time Factors; United States; Up-Regulation

Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing. - Chami, Hassan A; Keyes, Michelle J; Vita, Joseph A; Mitchell, Gary F; Larson, Martin G; Fan, Shuxia; Vasan, Ramachandran S; O'Connor, George T; Benjamin, Emelia J; Gottlieb, Daniel J (Vasc Med, 2009)
Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race- and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, >/= 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.
Keywords: Adult; Aged; Aged, 80 and over; Blood Flow Velocity; Brachial Artery; Cross-Sectional Studies; Female; Humans; Hyperemia; Hypoxia; Laser-Doppler Flowmetry; Male; Middle Aged; Polysomnography; Regional Blood Flow; Severity of Illness Index; Sleep Apnea Syndromes; Ultrasonography; Vasodilation

Change in cardiovascular risk factors with progression of kidney disease. - Fried, Linda F; Katz, Ronit; Cushman, Mary; Sarnak, Mark; Shlipak, Michael G; Kuller, Lewis; Newman, Anne B (Am J Nephrol, 2009)
BACKGROUND: Prior studies evaluating the relationship of kidney disease with cardiovascular risk factors have been limited by their cross-sectional design. We evaluated the change in lipids, inflammatory and procoagulant biomarkers with decline in kidney function in a nested case-cohort study in the Cardiovascular Health Study, a community-based study of adults aged >65 years. METHODS: Individuals with an increase in serum creatinine >or=0.3 mg/dl (baseline to 3 years later, n = 207) were matched to controls of similar age, race, gender, diabetes and baseline serum creatinine, but whose change in creatinine was <0.3 mg/dl. Baseline and change in risk factors were analyzed with conditional logistic regression. RESULTS: Changes in C-reactive protein were similar. In contrast, cases had larger increases in fibrinogen (OR 1.38 per standard deviation, 95% confidence interval 1.08-1.76) and factor VIII [1.38 (1.10-1.72)] and larger decreases in HDL [OR 0.80 (0.64, 1.00)]. Change in interleukin-6 was greater in cases than controls, but this did not persist after multivariate adjustment. However, in linear regression, change in interleukin-6 was correlated with change in creatinine. CONCLUSION: Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.
Keywords: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cholesterol, HDL; Creatinine; Diabetes Mellitus; Factor VIII; Female; Follow-Up Studies; Humans; Hypertension, Renal; Interleukin-6; Logistic Models; Male; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Vasculitis

Clinical and subclinical cardiovascular disease and kidney function decline in the elderly. - Shlipak, Michael G; Katz, Ronit; Kestenbaum, Bryan; Fried, Linda F; Siscovick, David; Sarnak, Mark J (Atherosclerosis, 2009)
OBJECTIVE: Kidney function decline in elderly persons may be the result of microvascular atherosclerosis. As a proxy for the renovascular system, we evaluated the association of clinical and subclinical cardiovascular disease (CVD) with kidney function decline. METHODS: This study included 4380 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged >or=65 from 4 U.S. communities. Creatinine and cystatin C were measured at baseline, year 3, and year 7; eligible subjects had at least two measures. Creatinine-based estimated glomerular filtration rate (eGFR(creat)) was calculated using the MDRD equation. Rapid kidney function decline was defined as an annual eGFR loss >3 mL/min/1.73 m(2). Predictors of rapid kidney decline included prevalent and subclinical measures of CVD. RESULTS: Mean decline in eGFR(creat) was 0.4+/-2.6/year; 714 (16%) had rapid progression. In multivariate models adjusted for demographics, cardiovascular risk factors, and inflammation, prevalent stroke (OR, 95% CI: 1.55, 1.16-2.08) and heart failure (OR, 95% CI: 1.80, 1.40-2.31) were independent predictors of rapid kidney decline. Among persons without clinical CV, the subclinical disease measures ankle-arm index <0.9 (OR, 95% CI: 1.67, 1.25-2.24), common carotid intima-media thickness (>or=1.14 mm) (OR, 95% CI: 1.52, 1.12-2.06) and internal carotid intima-media thickness (>1.82 mm) (OR, 95% CI: 1.50, 1.12-2.02) had independent associations with rapid kidney function decline. Results were similar using cystatin C. CONCLUSION: Clinical atherosclerosis and heart failure and subclinical measures of CVD have independent associations with kidney function decline progression in the elderly, suggesting an underlying role of renal atherosclerosis.
Keywords: Age Factors; Aged; Atherosclerosis; Cardiovascular Diseases; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Kidney Diseases; Linear Models; Longitudinal Studies; Male; Odds Ratio; Risk Assessment; Risk Factors; Time Factors; United States

Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. - Cushman, Mary; O'Meara, Ellen S; Folsom, Aaron R; Heckbert, Susan R (Blood, 2009)
Higher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Factor IX; Factor X; Factor XI; Factor XII; Factor XIII; Female; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Prospective Studies; Risk Factors; Venous Thromboembolism

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. - Psaty, Bruce M; O'Donnell, Christopher J; Gudnason, Vilmundur; Lunetta, Kathryn L; Folsom, Aaron R; Rotter, Jerome I; Uitterlinden, André G; Harris, Tamara B; Witteman, Jacqueline C M; Boerwinkle, Eric (Circ Cardiovasc Genet, 2009)
BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
Keywords: Adult; Aged; Aging; Cohort Studies; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Heart Diseases; Humans; Male; Meta-Analysis as Topic; Middle Aged; Phenotype; Research Design; Risk Factors

Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula - Reiner, Alexander P; Gross, Myron D; Carlson, Christopher S; Bielinski, Suzette J; Lange, Leslie A; Fornage, Myriam; Jenny, Nancy S; Walston, Jeremy; Tracy, Russell P; Williams, O Dale; Jacobs, David R; Nickerson, Deborah A (Circ Cardiovasc Genet, 2009)
BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 alpha regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 alpha gene (HNF1A) were recently associated with plasma C-reactive protein and gamma-glutamyl transferase concentration in middle-aged to older European Americans (EA). METHODS AND RESULTS: We assessed whether common variants of HNF1A are associated with C-reactive protein, gamma-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and gamma-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA. CONCLUSIONS: Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.
Keywords: Adolescent; Adult; African Americans; Aged; Aged, 80 and over; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Cohort Studies; European Continental Ancestry Group; Female; Fibrinogen; gamma-Glutamyltransferase; Genetic Predisposition to Disease; Genotype; Hepatocyte Nuclear Factor 1-alpha; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors

Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study. - Reiner, A P; Lange, L A; Smith, N L; Zakai, N A; Cushman, M; Folsom, A R (J Thromb Haemost, 2009)
BACKGROUND/OBJECTIVES: Age-related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages. METHODS: We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years. RESULTS: There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor-1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P-value < 0.05 and at least one tagSNP false discovery rate (FDR) q-value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66-fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49-0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha-fibrinogen and protein C genes and risk of VTE. CONCLUSIONS: These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.
Keywords: Aged; Alleles; Factor V; Factor VIII; Female; Hemostasis; Humans; Inflammation; Male; Middle Aged; Models, Genetic; Plasminogen; Prothrombin; Risk; Serine Endopeptidases; Venous Thrombosis

Common variants at ten loci influence QT interval duration in the QTGEN Study. - Newton-Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth M; de Bakker, Paul I W; Yin, Xiaoyan; Estrada, Karol; Bis, Joshua C; Marciante, Kristin; Rivadeneira, Fernando; Noseworthy, Peter A; Sotoodehnia, Nona; Smith, Nicholas L; et al. (Nat Genet, 2009)
QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
Keywords: Adaptor Proteins, Signal Transducing; Adult; Aged; Arrhythmias, Cardiac; Chromosome Mapping; Death, Sudden, Cardiac; Electroencephalography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; European Continental Ancestry Group; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Humans; KCNQ1 Potassium Channel; Meta-Analysis as Topic; Muscle Proteins; NAV1.5 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Potassium Channels, Voltage-Gated; Risk Factors; Sodium Channels

Correcting for multivariate measurement error by regression calibration in meta-analyses of epidemiological studies. (Stat Med, 2009)
Within-person variability in measured values of multiple risk factors can bias their associations with disease. The multivariate regression calibration (RC) approach can correct for such measurement error and has been applied to studies in which true values or independent repeat measurements of the risk factors are observed on a subsample. We extend the multivariate RC techniques to a meta-analysis framework where multiple studies provide independent repeat measurements and information on disease outcome. We consider the cases where some or all studies have repeat measurements, and compare study-specific, averaged and empirical Bayes estimates of RC parameters. Additionally, we allow for binary covariates (e.g. smoking status) and for uncertainty and time trends in the measurement error corrections. Our methods are illustrated using a subset of individual participant data from prospective long-term studies in the Fibrinogen Studies Collaboration to assess the relationship between usual levels of plasma fibrinogen and the risk of coronary heart disease, allowing for measurement error in plasma fibrinogen and several confounders.
Keywords: Bias; Cardiovascular Diseases; Epidemiologic Studies; Fibrinogen; Meta-Analysis as Topic; Models, Statistical; Multivariate Analysis; Regression Analysis

C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. - Pierce, Brandon L; Biggs, Mary L; DeCambre, Marvalyn; Reiner, Alexander P; Li, Christopher; Fitzpatrick, Annette; Carlson, Christopher S; Stanford, Janet L; Austin, Melissa A (Cancer Causes Control, 2009)
Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and the subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men of ages >64 years (n = 2,234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs that are known to associate with circulating CRP and/or IL-6. Neither CRP nor IL-6 blood concentrations was associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR = 1.44; 95% CI = 1.03-2.01; p = 0.03), but was not statistically significant after accounting for multiple tests (permutation p = 0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.
Keywords: African Americans; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; European Continental Ancestry Group; Humans; Inflammation; Interleukin-6; Male; Polymorphism, Single Nucleotide; Prospective Studies; Prostatic Neoplasms; Risk Factors

Cystatin C, albuminuria, and mortality among older adults with diabetes. - de Boer, Ian H; Katz, Ronit; Cao, Jie J; Fried, Linda F; Kestenbaum, Bryan; Mukamal, Ken; Rifkin, Dena E; Sarnak, Mark J; Shlipak, Michael G; Siscovick, David S (Diabetes Care, 2009)
OBJECTIVE: Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population. RESEARCH DESIGN AND METHODS: This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples. RESULTS: Of 691 participants, 378 died over 10 years of follow-up. Cystatin C-estimated GFR <60 ml/min per 1.73 m(2), creatinine-based estimated GFR <60 ml/min per 1.73 m(2), and urine ACR > or =30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37-2.18), 1.54 (1.21-1.97), and 1.73 (1.39-2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C-estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C-estimated GFR predicted mortality more strongly than creatinine-based estimated GFR. CONCLUSIONS: Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.
Keywords: Aged; Aged, 80 and over; Albuminuria; Creatinine; Cystatin C; Diabetes Mellitus; Female; Glomerular Filtration Rate; Humans; Kidney Function Tests; Male; Risk Factors

Depressed mood is not a risk factor for incident dementia in a community-based cohort. - Becker, James T; Chang, Yue-Fang; Lopez, Oscar L; Dew, Mary Amanda; Sweet, Robert A; Barnes, Deborah; Yaffe, Kristine; Young, Jeffrey; Kuller, Lewis; Reynolds, Charles F (Am J Geriatr Psychiatry, 2009)
OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals. DESIGN: Longitudinal and observational. SETTING: Community-based cohort study. PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years). MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams. RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood. CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Dementia; Depression; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Prospective Studies; Psychiatric Status Rating Scales; Residence Characteristics; Risk Factors

Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study. - Baker, Michelle L; Wang, Jie Jin; Rogers, Sophie; Klein, Ronald; Kuller, Lewis H; Larsen, Emily K; Wong, Tien Yin (Arch Ophthalmol, 2009)
OBJECTIVE: To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals. METHODS: This population-based study included 2,088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing. RESULTS: After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores, < or =30) were more likely to have early AMD (odds ratio, 1.38; 95% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD. CONCLUSIONS: In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cognition Disorders; Dementia; Female; Humans; Intelligence Tests; Macular Degeneration; Male; Neuropsychological Tests; Odds Ratio; Prospective Studies; Risk Factors; United States

External validity of the cardiovascular health study: a comparison with the Medicare population. - DiMartino, Lisa D; Hammill, Bradley G; Curtis, Lesley H; Gottdiener, John S; Manolio, Teri A; Powe, Neil R; Schulman, Kevin A (Med Care, 2009)
BACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly. OBJECTIVE: To assess the external validity of the CHS. RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions. SUBJECTS: CHS participants and a 5% sample of Medicare beneficiaries. MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality. RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40% lower at 1 year, approximately 25% lower at 5 years, and approximately 15% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use. CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.
Keywords: Aged; Cardiovascular Diseases; Cohort Studies; Comorbidity; Female; Humans; Male; Medicare; Randomized Controlled Trials as Topic; Reproducibility of Results; Socioeconomic Factors; United States

Gene variants associated with ischemic stroke: the cardiovascular health study. - Luke, May M; O'Meara, Ellen S; Rowland, Charles M; Shiffman, Dov; Bare, Lance A; Arellano, Andre R; Longstreth, W T; Lumley, Thomas; Rice, Kenneth; Tracy, Russell P; Devlin, James J; Psaty, Bruce M (Stroke, 2009)
BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke. METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS). RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS. CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
Keywords: African Continental Ancestry Group; Aged; Alleles; Brain Ischemia; Cardiovascular Diseases; Coronary Disease; Ethnic Groups; European Continental Ancestry Group; Female; Gene Frequency; Genetic Variation; Humans; Kaplan-Meier Estimate; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Stroke; United States

Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. - Vasan, Ramachandran S; Glazer, Nicole L; Felix, Janine F; Lieb, Wolfgang; Wild, Philipp S; Felix, Stephan B; Watzinger, Norbert; Larson, Martin G; Smith, Nicholas L; Dehghan, Abbas; Grosshennig, Anika; Schillert, Arne; et al. (JAMA, 2009)
CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
Keywords: Adult; Aged; Aged, 80 and over; Aorta; Cardiovascular Diseases; Echocardiography; European Continental Ancestry Group; Female; Genome-Wide Association Study; Genotype; Heart Atria; Heart Ventricles; Humans; Male; Middle Aged; Organ Size; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. - Kao, W H Linda; Arking, Dan E; Post, Wendy; Rea, Thomas D; Sotoodehnia, Nona; Prineas, Ronald J; Bishe, Bryan; Doan, Betty Q; Boerwinkle, Eric; Psaty, Bruce M; Tomaselli, Gordon F; Coresh, Josef; et al. (Circulation, 2009)
BACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks. CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.
Keywords: Adaptor Proteins, Signal Transducing; Aged; Death, Sudden, Cardiac; Electrocardiography; European Continental Ancestry Group; Genotype; Humans; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretation. - Bis, J C; Glazer, N L; Psaty, B M (J Thromb Haemost, 2009)
Relying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.
Keywords: Cardiovascular Diseases; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Quantitative Trait Loci; Risk Factors

Genomewide association studies of stroke. - Ikram, M Arfan; Seshadri, Sudha; Bis, Joshua C; Fornage, Myriam; DeStefano, Anita L; Aulchenko, Yurii S; Debette, Stephanie; Lumley, Thomas; Folsom, Aaron R; van den Herik, Evita G; Bos, Michiel J; Beiser, Alexa; et al. (N Engl J Med, 2009)
BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
Keywords: African Continental Ancestry Group; Aged; Chromosomes, Human, Pair 12; Cohort Studies; European Continental Ancestry Group; Female; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk Factors; Stroke

Genome-wide association study of blood pressure and hypertension. - Levy, Daniel; Ehret, Georg B; Rice, Kenneth; Verwoert, Germaine C; Launer, Lenore J; Dehghan, Abbas; Glazer, Nicole L; Morrison, Alanna C; Johnson, Andrew D; Aspelund, Thor; Aulchenko, Yurii; Lumley, Thomas; et al. (Nat Genet, 2009)
Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
Keywords: Blood Pressure; Cell Line; Chromosome Mapping; Chromosomes, Human; Diastole; Gene Expression Regulation; Genetic Association Studies; Genome-Wide Association Study; Humans; Hypertension; Liver; Lymphocytes; Meta-Analysis as Topic; Odds Ratio; Phenotype; Prevalence; Risk Assessment; Systole

Heart rate variability and its changes over 5 years in older adults. - Stein, Phyllis K; Barzilay, Joshua I; Chaves, Paulo H M; Domitrovich, Peter P; Gottdiener, John S (Age Ageing, 2009)
PURPOSE: to characterise the association between age, ageing and heart rate variability (HRV) in older individuals, 585 adults age >65 years with two 24-h Holter recordings in the Cardiovascular Health Study were studied. METHODS: heart rate (HR), ventricular premature contractions (VPCs), atrial premature contractions (APCs), frequency-domain, ratio-based and non-linear HRV and heart rate turbulence (HRT) were examined cross-sectionally by 5-year age groups and prospectively over 5 years. Analyses adjusted for gender, lower versus elevated cardiovascular (CV) risk and for the change in CV risk. RESULTS: HR declined, and VPCs and APCs increased per 5-year increase in age. Frequency-domain HRV decreased more at 65-69, less at 70-74 and minimally at > or =75 years, independent of CVD risk or change in CVD risk. Ratio and non-linear HRV continued to decline to > or =75 years old. Ratio HRV and HRT slope were more strongly related to CVD risk than frequency-domain HRV. CONCLUSIONS: cardiac autonomic function, assessed by frequency-domain HRV, declines most at 65-70 and levels off at age >75. The decline is independent of CVD risk or change in CVD risk. Ratio-based and non-linear HRV and HRT slope continued to change with increasing age and were more closely related to CVD risk than frequency-domain HRV.
Keywords: Age Distribution; Aged; Aging; Atrial Premature Complexes; Autonomic Nervous System; Cardiovascular Diseases; Cross-Sectional Studies; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Hypertension; Male; Nonlinear Dynamics; Prevalence; Prospective Studies; Risk Factors; Ventricular Premature Complexes

High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. - Somwaru, Lily L; Arnold, Alice M; Joshi, Neha; Fried, Linda P; Cappola, Anne R (J Clin Endocrinol Metab, 2009)
CONTEXT: Thyroid hormone use is common in older populations, but the frequency of over- or under-replacement is debated. OBJECTIVE: We sought to describe the frequency of and factors associated with thyroid hormone over- or under-replacement in a population of older men and women. DESIGN: Participants were 3678 U.S. community dwelling individuals aged 65 yr or older enrolled in the Cardiovascular Health Study who had thyroid function tests in 1989-1990. Thyroid hormone users (n = 339) were identified and classified into low TSH (<0.45 mU/liter), euthyroid (0.45-4.5 mU/liter), and high TSH (>4.5 mU/liter). RESULTS: Of the 339 thyroid hormone users, 41% had a low TSH, 16% had a high TSH, and 43% were in the euthyroid range. In multivariable analyses, lower weight (P < 0.001) was independently associated with low TSH status. For every 10 kg lower weight, the likelihood of having low TSH increased by 65% [odd ratio (OR) 1.65; 95% confidence interval (CI) 1.31-2.07]. Those with renal insufficiency were less likely to have low TSH levels (P = 0.02). The presence of diabetes was independently associated with having low (OR 3.35; 95% CI 1.46-7.65) and high TSH levels (OR 2.66; 95% CI 1.14-6.21). CONCLUSIONS: There is a very high prevalence of thyroid function testing abnormalities in older people taking thyroid hormone preparations, particularly in those of low weight or with diabetes. Because of potential adverse cardiovascular and skeletal effects from over-replacement, older people represent a key population for increased TSH monitoring on therapy.
Keywords: Aged; Body Mass Index; Body Weight; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hormone Replacement Therapy; Humans; Male; Multivariate Analysis; Renal Insufficiency; Risk Factors; Thyroid Diseases; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. - Patel, Shrita M; Ratcliffe, Sarah J; Reilly, Muredach P; Weinstein, Rachel; Bhasin, Shalender; Blackman, Marc R; Cauley, Jane A; Sutton-Tyrrell, Kim; Robbins, John; Fried, Linda P; Cappola, Anne R (J Clin Endocrinol Metab, 2009)
CONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown. OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women. DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD. RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD. CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.
Keywords: Aged; Aged, 80 and over; Blood Glucose; Cardiovascular Diseases; Coronary Disease; Female; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Odds Ratio; Radioimmunoassay; Socioeconomic Factors; Testosterone; Treatment Outcome

Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study. - Sun, C; Wang, J J; Islam, F M; Heckbert, S R; Klein, R; Siscovick, D S; Klein, B E K; Wong, T Y (J Hum Hypertens, 2009)
We examined the associations of single nucleotide polymorphisms (SNPs) in three candidate hypertension genes, alpha-adducin (ADD1/G460W), beta2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein beta3 subunit (GNB3/C825T), with retinal arteriolar calibre (an intermediate marker of chronic hypertension) and venular calibre. Data in 1842 participants (1554 whites and 288 African Americans) aged 69-96 years from the Cardiovascular Health Study with genotype and retinal vascular calibre data were included. A computer-assisted method was used to measure retinal vascular calibre. We analysed four SNPs and multilocus interaction for three genes. All SNPs were in Hardy-Weinberg equilibrium in whites and African Americans. The study had sufficient power to detect 0.5% of the total variance of retinal vascular calibre contributed by each SNP in the total population, except for the GNB3 gene variant. No significant associations between these SNPs in the genes studied and mean retinal arteriolar and venular calibre were found in single-gene or multilocus analysis (for example, age-, gender-, race-adjusted mean retinal arteriolar calibre was similar between participants who were ADD1/460W homozygotes and ADD1/G allele carriers, 166.2 vs 167.7 microm). In conclusion, this study found no evidence of an association of SNPs in candidate hypertension genes studied here with retinal vascular calibre.
Keywords: African Americans; Aged; Aged, 80 and over; Arterioles; Calmodulin-Binding Proteins; European Continental Ancestry Group; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Longitudinal Studies; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2; Retinal Vessels

Imaging cerebral blood flow in the cognitively normal aging brain with arterial spin labeling: implications for imaging of neurodegenerative disease. - Lee, Charles; Lopez, Oscar L; Becker, James T; Raji, Cyrus; Dai, Weiying; Kuller, Lewis H; Gach, H Michael (J Neuroimaging, 2009)
INTRODUCTION: Arterial spin labeling (ASL) is a safe, noninvasive imaging method for evaluating cerebral blood flow (rCBF). The purpose of this article is to present ASL imaging features of 38 elderly cognitively normals (CN) with their rCBF values and an averaged profile of targeted anatomic regions rCBF values. METHODS: Thirty-eight CN underwent MR imaging especially ASL with voxel morphometric techniques fusing the MR anatomical and ASL images to a standard reference brain (colin27). The ASL images were fused to echo planar images, which were then coregistered to high-resolution anatomical SPGR images. rCBF was calculated per region of interest using a modified continuous arterial spin labeling (CASL) convolutional method. Anatomical regions were selected and identified by the Talairach atlas in SPM2. RESULTS: We identified areas of decreased and increased perfusion (compared to the averaged rCBF of all 38 CN) corresponding to decreased and increased quantified rCBF. The most common sites for decreased perfusion were precuneus (53%), superior temporal (48%), and orbitofrontal (37%), and for increased perfusion the caudate (39%), posterior cingulate (34%), anterior cingulate (32%), and amygdala (32%). CONCLUSION: There are regional variations in rCBF both increased and decreased with the posterior cingulate and precuneus cortex showing the highest averaged values and signal intensity (bright spots). These variations represent the normal profile of a CN elderly brain, with higher perfusion in areas associated with cognition, memory, and behavior. It is necessary to understand these normal variations in order to determine if there are perfusion changes in ASL detected in neurodegenerative disorders such as Alzheimer's disease.
Keywords: Aged, 80 and over; Aging; Brain; Brain Mapping; Cerebrovascular Circulation; Female; Humans; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Signal Processing, Computer-Assisted; Spin Labels

Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. - Walston, Jeremy D; Matteini, Amy M; Nievergelt, Caroline; Lange, Leslie A; Fallin, Dani M; Barzilai, Nir; Ziv, Elad; Pawlikowska, Ludmila; Kwok, Pui; Cummings, Steve R; Kooperberg, Charles; LaCroix, Andrea; et al. (Exp Gerontol, 2009)
Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
Keywords: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Case-Control Studies; Female; Genetic Variation; Genotype; Humans; Inflammation; Interleukin-6; Longevity; Male; Phenotype; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Risk Factors

Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. - Phillips, Barbara; Bůzková, Petra; Enright, Paul (Sleep, 2009)
STUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction. DESIGN: This is a prospective cohort study over a 6-year period of follow-up. SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland. PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline. INTERVENTIONS: none. MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination. RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans. CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.
Keywords: African Americans; Aged; Cohort Studies; Comorbidity; European Continental Ancestry Group; Female; Follow-Up Studies; Health Surveys; Humans; Hypertension; Male; Prospective Studies; Risk Factors; Sleep Initiation and Maintenance Disorders; United States

Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study. - Kaplan, Robert C; Fitzpatrick, Annette L; Pollak, Michael N; Gardner, Jeffrey P; Jenny, Nancy S; McGinn, Aileen P; Kuller, Lewis H; Strickler, Howard D; Kimura, Masayuki; Psaty, Bruce M; Aviv, Abraham (J Gerontol A Biol Sci Med Sci, 2009)
The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.
Keywords: Aged; Aging; Cross-Sectional Studies; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leukocytes; Linear Models; Male; Sex Characteristics; Telomere

Joint modeling of self-rated health and changes in physical functioning. - Hubbard, Rebecca A; Inoue, Lurdes Y T; Diehr, Paula (J Am Stat Assoc, 2009)
Self-rated health is an important indicator of future morbidity and mortality. Past research has indicated that self-rated health is related to both levels of and changes in physical functioning. However, no previous study has jointly modeled longitudinal functional status and self-rated health trajectories. We propose a joint model for self-rated health and physical functioning that describes the relationship between perceptions of health and the rate of change of physical functioning or disability. Our joint model uses a non-homogeneous Markov process for discrete physical functioning states and connects this to a logistic regression model for "healthy" versus "unhealthy" self-rated health through parameters of the physical functioning model. We use simulation studies to establish finite sample properties of our estimators and show that this model is robust to misspecification of the functional form of the relationship between self-rated health and rate of change of physical functioning. We also show that our joint model performs better than an empirical model based on observed changes in functional status. We apply our joint model to data from the Cardiovascular Health Study (CHS), a large, multi-center, longitudinal study of older adults. Our analysis indicates that self-rated health is associated both with level of functioning as indicated by difficulty with activities of daily living (ADL) and instrumental activities of daily living (IADL), and the risk of increasing difficulty with ADLs and IADLs.

Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. - Yamagishi, Kazumasa; Cushman, Mary; Heckbert, Susan R; Tsai, Michael Y; Folsom, Aaron R (Br J Haematol, 2009)
Prior case-control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged > or =45 years. A nested case-control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1.17[0.86-1.59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1.84[1.05-3.22]) and women (OR = 1.51[1.01-2.26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0.93[0.70-1.25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.
Keywords: Antigens, CD; Case-Control Studies; Endothelial Protein C Receptor; Female; Genotype; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Prospective Studies; Receptors, Cell Surface; Risk; Venous Thromboembolism

Left atrial volume and geometry in healthy aging: the Cardiovascular Health Study. - Aurigemma, Gerard P; Gottdiener, John S; Arnold, Alice M; Chinali, Marcello; Hill, Jeffrey C; Kitzman, Dalane (Circ Cardiovasc Imaging, 2009)
BACKGROUND: The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement. METHODS AND RESULTS: We evaluated left atrial size in 230 healthy participants (mean age, 76+/-5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build. CONCLUSIONS: These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Atrial Function, Left; Body Size; Body Surface Area; Echocardiography, Three-Dimensional; Female; Heart Atria; Humans; Linear Models; Male; Models, Biological; Organ Size; Population Surveillance; Prospective Studies; Reference Values; Sex Factors; United States

Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. - Mozaffarian, Dariush; Kamineni, Aruna; Carnethon, Mercedes; Djoussé, Luc; Mukamal, Kenneth J; Siscovick, David (Arch Intern Med, 2009)
BACKGROUND: The combined impact of lifestyle factors on incidence of diabetes mellitus later in life is not well established. The objective of this study was to determine how lifestyle factors, assessed in combination, relate to new-onset diabetes in a broad and relatively unselected population of older adults. METHODS: We prospectively examined associations of lifestyle factors, measured using repeated assessments later in life, with incident diabetes mellitus during a 10-year period (1989-1998) among 4883 men and women 65 years or older (mean [SD] age at baseline, 73 [6] years) enrolled in the Cardiovascular Health Study. Low-risk lifestyle groups were defined by physical activity level (leisure-time activity and walking pace) above the median; dietary score (higher fiber intake and polyunsaturated to saturated fat ratio, lower trans-fat intake and lower mean glycemic index) in the top 2 quintiles; never smoked or former smoker more than 20 years ago or for fewer than 5 pack-years; alcohol use (predominantly light or moderate); body mass index less than 25 (calculated as weight in kilograms divided by height in meters squared); and waist circumference of 88 cm for women or 92 cm for men. The main outcome measure was incident diabetes defined annually by new use of insulin or oral hypoglycemic medications. We also evaluated fasting and 2-hour postchallenge glucose levels. RESULTS: During 34,539 person-years, 337 new cases of drug-treated diabetes mellitus occurred (9.8 per 1000 person-years). After adjustment for age, sex, race, educational level, and annual income, each lifestyle factor was independently associated with incident diabetes. Overall, the rate of incident diabetes was 35% lower (relative risk, 0.65; 95% confidence interval, 0.59-0.71) for each 1 additional lifestyle factor in the low-risk group. Participants whose physical activity level and dietary, smoking, and alcohol habits were all in the low-risk group had an 82% lower incidence of diabetes (relative risk, 0.18; 95% confidence interval, 0.06-0.56) compared with all other participants. When absence of adiposity (either body mass index <25 or waist circumference < or =88/92 cm for women/men) was added to the other 4 low-risk lifestyle factors, incidence of diabetes was 89% lower (relative risk, 0.11; 95% confidence interval, 0.01-0.76). Overall, 9 of 10 new cases of diabetes appeared to be attributable to these 5 lifestyle factors. Associations were slightly attenuated, but still highly significant, for incident diabetes defined by medication use or glucose level. CONCLUSION: Even later in life, combined lifestyle factors are associated with a markedly lower incidence of new-onset diabetes mellitus.
Keywords: Age of Onset; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Life Style; Male; National Heart, Lung, and Blood Institute (U.S.); Prospective Studies; Risk Factors; United States

Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. - Erqou, Sebhat; Kaptoge, Stephen; Perry, Philip L; Di Angelantonio, Emanuele; Thompson, Alexander; White, Ian R; Marcovina, Santica M; Collins, Rory; Thompson, Simon G; Danesh, John (JAMA, 2009)
CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
Keywords: Cause of Death; Coronary Disease; Humans; Lipoprotein(a); Risk Factors; Stroke

Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study. - Suzuki, Takeki; Solomon, Cam; Jenny, Nancy Swords; Tracy, Russell; Nelson, Jeanenne J; Psaty, Bruce M; Furberg, Curt; Cushman, Mary (Circ Heart Fail, 2009)
BACKGROUND: Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA(2) activity with CHF risk, but there were only 94 CHF cases and Lp-PLA(2) antigen, which is available clinically in the United States, was not measured. METHODS AND RESULTS: We measured baseline Lp-PLA(2) antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA(2) in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA(2) antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA(2) antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact. CONCLUSIONS: Lp-PLA(2) antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA(2) in CHF.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Biomarkers; C-Reactive Protein; Female; Fibrinogen; Heart Failure; Humans; Incidence; Inflammation Mediators; Interleukin-6; Kaplan-Meier Estimate; Male; Population Surveillance; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; United States

Longitudinal Data with Follow-up Truncated by Death: Match the Analysis Method to Research Aims. - Kurland, Brenda F; Johnson, Laura L; Egleston, Brian L; Diehr, Paula H (Stat Sci, 2009)
Diverse analysis approaches have been proposed to distinguish data missing due to death from nonresponse, and to summarize trajectories of longitudinal data truncated by death. We demonstrate how these analysis approaches arise from factorizations of the distribution of longitudinal data and survival information. Models are illustrated using cognitive functioning data for older adults. For unconditional models, deaths do not occur, deaths are independent of the longitudinal response, or the unconditional longitudinal response is averaged over the survival distribution. Unconditional models, such as random effects models fit to unbalanced data, may implicitly impute data beyond the time of death. Fully conditional models stratify the longitudinal response trajectory by time of death. Fully conditional models are effective for describing individual trajectories, in terms of either aging (age, or years from baseline) or dying (years from death). Causal models (principal stratification) as currently applied are fully conditional models, since group differences at one timepoint are described for a cohort that will survive past a later timepoint. Partly conditional models summarize the longitudinal response in the dynamic cohort of survivors. Partly conditional models are serial cross-sectional snapshots of the response, reflecting the average response in survivors at a given timepoint rather than individual trajectories. Joint models of survival and longitudinal response describe the evolving health status of the entire cohort. Researchers using longitudinal data should consider which method of accommodating deaths is consistent with research aims, and use analysis methods accordingly.

Longitudinal evaluation of sleep-disordered breathing and sleep symptoms with change in quality of life: the Sleep Heart Health Study (SHHS). - Silva, Graciela E; An, Ming-Wen; Goodwin, James L; Shahar, Eyal; Redline, Susan; Resnick, Helaine; Baldwin, Carol M; Quan, Stuart F (Sleep, 2009)
STUDY OBJECTIVES: Findings from population studies evaluating the progression and incidence of sleep disordered breathing have shown evidence of a longitudinal increase in the severity of sleep disordered breathing. The present study evaluates the association among changes in sleep disordered breathing, sleep symptoms, and quality of life over time. DESIGN: Prospective cohort study. Data were from the Sleep Heart Health Study. SETTING: Multicenter study. PARTICIPANTS: Three thousand seventy-eight subjects aged 40 years and older from the baseline and follow-up examination cycles were included. MEASUREMENTS: The primary outcomes were changes in the Physical Component Summary and Mental Component Summary scales obtained from the Medical Outcomes Study Short-Form Health Survey. The primary exposure was change in the respiratory disturbance index obtained from unattended overnight polysomnograms performed approximately 5 years apart. Other covariates included measures of excessive daytime sleepiness and difficulty initiating and maintaining sleep. RESULTS: Mean respiratory disturbance index increased from 8.1 +/- 11 SD at baseline to 10.9 +/- 14 (P < 0.0001) at follow-up. The mean Physical Component Summary and Mental Component Summary scores were 48.5 and 54.1 at baseline and 46.3 and 54.8 at follow-up. No associations between change in respiratory disturbance index and changes in Physical Component Summary or Mental Component Summary scores were seen. However, worsening of difficulty initiating and maintaining sleep and excessive daytime sleepiness were significantly associated with lower quality of life. CONCLUSIONS: A slight increase in severity of sleep disordered breathing was seen over 5 years; this was not associated with worsening of quality of life. However, subjective symptoms of quality of sleep and daytime sleepiness were associated with declining quality of life.
Keywords: Aged; Attitude to Health; Cohort Studies; Comorbidity; Disease Progression; Disorders of Excessive Somnolence; Female; Humans; Longitudinal Studies; Male; Middle Aged; Polysomnography; Quality of Life; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders

Long-term function in an older cohort--the cardiovascular health study all stars study. - Newman, Anne B; Arnold, Alice M; Sachs, Michael C; Ives, Diane G; Cushman, Mary; Strotmeyer, Elsa S; Ding, Jingzhong; Kritchevsky, Stephen B; Chaves, Paulo H M; Fried, Linda P; Robbins, John (J Am Geriatr Soc, 2009)
OBJECTIVES: To evaluate shared and unique risk factors for maintaining physical and cognitive function into the ninth decade and beyond. DESIGN: Longitudinal cohort study. SETTING: Four U.S. communities. PARTICIPANTS: One thousand six hundred seventy-seven participants in the Cardiovascular Health Study All Stars Study, assessed in 2005/06. Median age was 85 (range 77-102), 66.5% were women, and 16.6% were black. MEASUREMENTS: Intact function was defined as no difficulty with any activities of daily living and a score of 80 or higher on the Modified Mini-Mental State Examination. Baseline characteristics assessed in 1992/93 included demographics, behavioral health factors, chronic disease history, subclinical disease markers, cardiovascular risk factors, and inflammatory markers. Multinomial logistic regression was used to compare risk for physical disability, cognitive impairment,and combined impairments with no functional impairment. RESULTS: Of the 1,677 participants evaluated in both domains, 891 (53%) were functionally intact. Continuous measures of function, including the Digit Symbol Substitution Test and gait speed, showed that all groups, including the most functional, had declined over time. The functional group had less decline but also tended to have higher starting values. Functional individuals had a higher baseline health profile than those with either or cognitive impairment or both impairments combined. Women and individuals with greater weight had higher rates of physical impairment but not cognitive impairment. Risk factors common to both types of impairment included cardiovascular disease and hypertension. CONCLUSION: Intact function was found in only approximately half of these older adults in the ninth decade and beyond. High baseline function and low vascular disease risk characterized functional aging.
Keywords: Activities of Daily Living; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Cardiovascular Diseases; Chronic Disease; Cohort Studies; Comorbidity; Cross-Sectional Studies; Female; Follow-Up Studies; Gait; Geriatric Assessment; Hand Strength; Health Surveys; Humans; Male; Memory, Short-Term; Mental Status Schedule; Proportional Hazards Models; Psychometrics; Risk Factors; United States

Meta-analysis: retinal vessel caliber and risk for coronary heart disease. - McGeechan, Kevin; Liew, Gerald; Macaskill, Petra; Irwig, Les; Klein, Ronald; Klein, Barbara E K; Wang, Jie Jin; Mitchell, Paul; Vingerling, Johannes R; Dejong, Paulus T V M; Witteman, Jacqueline C M; Breteler, Monique M B; et al. (Ann Intern Med, 2009)
BACKGROUND: Retinal vessel caliber may be a novel marker of coronary heart disease (CHD) risk. However, the sex-specific effect, magnitude of association, and effect independent of traditional CHD disease risk factors remain unclear. PURPOSE: To determine the association between retinal vessel caliber and risk for CHD. DATA SOURCES: Relevant studies in any language identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases. STUDY SELECTION: Studies were included if they examined a general population, measured retinal vessel caliber from retinal photographs, and documented CHD risk factors and incident CHD events. DATA EXTRACTION: 6 population-based prospective cohort studies provided data for individual participant meta-analysis. DATA SYNTHESIS: Proportional hazards models, adjusted for traditional CHD risk factors, were constructed for retinal vessel caliber and incident CHD in women and men. Among 22,159 participants who were free of CHD and followed for 5 to 14 years, 2219 (10.0%) incident CHD events occurred. Retinal vessel caliber changes (wider venules and narrower arterioles) were each associated with an increased risk for CHD in women (pooled multivariable-adjusted hazard ratios, 1.16 [95% CI, 1.06 to 1.26] per 20-microm increase in venular caliber and 1.17 [CI, 1.07 to 1.28] per 20-microm decrease in arteriolar caliber) but not in men (1.02 [CI, 0.94 to 1.10] per 20-microm increase in venular caliber and 1.02 [CI, 0.95 to 1.10] per 20-microm decrease in arteriolar caliber). Women without hypertension or diabetes had higher hazard ratios. LIMITATION: Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account. CONCLUSION: Retinal vessel caliber changes were independently associated with an increased risk for CHD events in women.
Keywords: Adult; Aged; Arterioles; Biomarkers; Coronary Disease; Female; Humans; Male; Middle Aged; Proportional Hazards Models; Retinal Vessels; Risk Factors; Sex Factors; Venules

Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. - Steffen, L M; Cushman, M; Peacock, J M; Heckbert, S R; Jacobs, D R; Rosamond, W D; Folsom, A R (J Thromb Haemost, 2009)
SUMMARY BACKGROUND: In a recent case-control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE. METHODS: A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including >or=3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p(interaction) = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders. RESULTS: Incident VTE (n = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components. CONCLUSION: Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.
Keywords: Blood Coagulation Factors; Blood Glucose; Blood Pressure; Body Mass Index; Cohort Studies; Female; Fibrinogen; Humans; Lipids; Longitudinal Studies; Male; Metabolic Syndrome; Proportional Hazards Models; Risk Factors; Venous Thromboembolism

Midlife and late-life obesity and the risk of dementia: cardiovascular health study. - Fitzpatrick, Annette L; Kuller, Lewis H; Lopez, Oscar L; Diehr, Paula; O'Meara, Ellen S; Longstreth, W T; Luchsinger, José A (Arch Neurol, 2009)
BACKGROUND: While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting. OBJECTIVE: To evaluate associations between midlife and late-life obesity and risk of dementia. DESIGN: Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999). SETTING: Community-dwelling sample in 4 US sites recruited from Medicare eligibility files. PARTICIPANTS: A total of 2798 adults without dementia (mean age, 74.7 years; 59.1% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times. MAIN OUTCOME MEASURES: Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria. RESULTS: Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI. CONCLUSION: These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Anthropometry; Body Mass Index; Dementia, Vascular; Evaluation Studies as Topic; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Obesity; Prospective Studies; Risk; Survival Analysis

Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging. - Dai, Weiying; Lopez, Oscar L; Carmichael, Owen T; Becker, James T; Kuller, Lewis H; Gach, H Michael (Radiology, 2009)
PURPOSE: To examine regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and Alzheimer disease (AD) by using continuous arterial spin-labeling (CASL) magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA regulations. Informed consent was obtained. rCBF was measured in 38 control subjects, 29 MCI patients, and 37 AD patients who were participating in a longitudinal epidemiologic study. Multisection CASL MR imaging with alternating single and double adiabatic inversion pulses and ramp-sampled echo-planar imaging were performed to acquire 19 contiguous axial sections. Voxel-level rCBF was compared among groups by using an analysis of variance design; clusters of voxels with significant group differences were identified. Multiple regression models controlled for age, sex, and presence of hypertension and related the mean rCBF in those clusters to the presence of MCI and AD. RESULTS: MCI and AD patients had decreased rCBF in the posterior cingulate gyrus (P = .01) with extension to the medial precuneus compared with that in control subjects. MCI patients had increased rCBF in the left hippocampus (P < .001), right amygdala (P = .007), and rostral head of the right caudate nucleus and ventral putamen and globus pallidus (P = .003) compared with that in control subjects. AD patients had decreased rCBF relative to that in control subjects and MCI patients in the left inferior parietal (P = .005), left lateral frontal (P < .001), left superior temporal (P = .001), and left orbitofrontal (P = .003) cortices. AD patients had increased rCBF in the right anterior cingulate gyrus (P = .02) compared with that in control subjects. CONCLUSION: The transition from normal cognition to AD is associated with dynamic pathologic processes in the brain, and this is reflected by both decreases and increases in rCBF. Increases in rCBF suggest a cellular and vascular compensatory process associated with incipient AD. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2503080751/DC1.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. - Arking, Dan E; Khera, Amit; Xing, Chao; Kao, W H Linda; Post, Wendy; Boerwinkle, Eric; Chakravarti, Aravinda (PLoS One, 2009)
Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.
Keywords: Adaptor Proteins, Signal Transducing; Adolescent; Adult; African Americans; Aged; Death, Sudden, Cardiac; Electrocardiography; Ethnic Groups; European Continental Ancestry Group; Female; Genome-Wide Association Study; Heart Diseases; Heart Rate; Hispanic Americans; Humans; Linear Models; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Sex Factors; Young Adult

Multiple loci associated with indices of renal function and chronic kidney disease. - Köttgen, Anna; Glazer, Nicole L; Dehghan, Abbas; Hwang, Shih-Jen; Katz, Ronit; Li, Man; Yang, Qiong; Gudnason, Vilmundur; Launer, Lenore J; Harris, Tamara B; Smith, Albert V; Arking, Dan E; et al. (Nat Genet, 2009)
Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
Keywords: Chromosome Mapping; Cohort Studies; Genetic Variation; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Meta-Analysis as Topic; Mucoproteins; Netherlands; Polymorphism, Single Nucleotide; Prevalence; Uromodulin

Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. - Ganesh, Santhi K; Zakai, Neil A; van Rooij, Frank J A; Soranzo, Nicole; Smith, Albert V; Nalls, Michael A; Chen, Ming-Huei; Köttgen, Anna; Glazer, Nicole L; Dehghan, Abbas; Kuhnel, Brigitte; Aspelund, Thor; et al. (Nat Genet, 2009)
Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
Keywords: Blood Pressure; Cell Line; Cohort Studies; Endothelial Cells; Erythrocytes; Gene Expression; Genome, Human; Genome-Wide Association Study; Humans; Hypertension; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci

NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. - Heard-Costa, Nancy L; Zillikens, M Carola; Monda, Keri L; Johansson, Asa; Harris, Tamara B; Fu, Mao; Haritunians, Talin; Feitosa, Mary F; Aspelund, Thor; Eiriksdottir, Gudny; Garcia, Melissa; Launer, Lenore J; et al. (PLoS Genet, 2009)
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
Keywords: Aged; Body Mass Index; Cohort Studies; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Nerve Tissue Proteins; Obesity; Polymorphism, Single Nucleotide; Waist Circumference

N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. - Patton, Kristen K; Ellinor, Patrick T; Heckbert, Susan R; Christenson, Robert H; DeFilippi, Christopher; Gottdiener, John S; Kronmal, Richard A (Circulation, 2009)
BACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality. METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95% confidence interval, 3.2 to 5.0; P<0.001). CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
Keywords: Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Immunoassay; Longitudinal Studies; Male; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prevalence; Proportional Hazards Models; Risk Factors

Obesity and change in estimated GFR among older adults. - de Boer, Ian H; Katz, Ronit; Fried, Linda F; Ix, Joachim H; Luchsinger, Jose; Sarnak, Mark J; Shlipak, Michael G; Siscovick, David S; Kestenbaum, Bryan (Am J Kidney Dis, 2009)
BACKGROUND: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 4,295 participants in the community-based Cardiovascular Health Study, aged >or= 65 years. PREDICTORS: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance. OUTCOME: Change in glomerular filtration rate (GFR) during 7 years of follow-up. MEASUREMENTS: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. RESULTS: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95% CI, 1.09-1.30) per 5 kg/m(2), 1.25 (95% CI, 1.16-1.36) per 12 cm, and 1.14 (95% CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level. LIMITATIONS: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements. CONCLUSION: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults.
Keywords: Aged; Aging; Body Composition; Body Mass Index; Chronic Disease; Cohort Studies; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Longitudinal Studies; Male; Obesity; Risk Factors

Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study. - Lutsey, P L; Folsom, A R; Heckbert, S R; Cushman, M (J Thromb Haemost, 2009)
BACKGROUND: Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin. OBJECTIVES: We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers. METHODS: The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer. RESULTS: Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28-2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05-2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time. CONCLUSIONS: In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.
Keywords: Adult; Aged; Biomarkers; Blood Coagulation Factors; Case-Control Studies; Ethnic Groups; Factor VIII; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Partial Thromboplastin Time; Prospective Studies; Risk Factors; Thrombin; United States; Venous Thromboembolism

Physical activity and rapid decline in kidney function among older adults. - Robinson-Cohen, Cassianne; Katz, Ronit; Mozaffarian, Dariush; Dalrymple, Lorien S; de Boer, Ian; Sarnak, Mark; Shlipak, Mike; Siscovick, David; Kestenbaum, Bryan (Arch Intern Med, 2009)
BACKGROUND: Habitual physical activity (PA) has both physiologic and metabolic effects that may moderate the risk of kidney function decline. We tested the hypothesis that higher levels of PA are associated with a lower risk of kidney function decline using longitudinal data from a large cohort of older adults. METHODS: We studied 4011 ambulatory participants aged 65 or older from the Cardiovascular Health Study (CHS) who completed at least 2 measurements of kidney function over 7 years. We calculated a PA score (range, 2-8) by summing kilocalories expended per week (ordinal score of 1-5 from quintiles of kilocalories per week) and walking pace (ordinal score for categories of <2, 2-3, and >3 mph). Rapid decline in kidney function decline (RDKF) was defined by loss of more than 3.0 mL/min/1.73 m(2) per year in glomerular filtration rate, which we estimated by using longitudinal measurements of cystatin C levels. RESULTS: A total of 958 participants had RDKF (23.9%; 4.1 events per 100 person-years). The estimated risk of RDKF was 16% in the highest PA group (score of 8) and 30% in the lowest PA group (score of 2). After multivariate adjustment, we found that the 2 highest PA groups (scores of 7-8) were associated with a 28% lower risk of RDKF (95% confidence interval, 21%-41% lower risk) than the 2 lowest PA groups (score of 2-3). Greater kilocalories of leisure-time PA and walking pace were also each associated with a lower incidence of RDKF. CONCLUSION: Higher levels of PA are associated with a lower risk of RDKF among older adults.
Keywords: Aged; Cystatin C; Female; Glomerular Filtration Rate; Humans; Kidney Function Tests; Longitudinal Studies; Male; Motor Activity; Renal Insufficiency; Time Factors

Platelet count and the risk for thrombosis and death in the elderly. - van der Bom, J G; Heckbert, S R; Lumley, T; Holmes, C E; Cushman, M; Folsom, A R; Rosendaal, F R; Psaty, B M (J Thromb Haemost, 2009)
AIM: Our aim was to examine the association between platelet count and the incidence of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thrombosis, and mortality. METHODS AND RESULTS: Platelet count was measured at baseline in 1989-1990 and at 3 years follow-up, or at baseline (for a newly recruited group) in 1992-1993 in 5766 community-dwelling individuals aged 65 years and older (mean age at baseline, 73 years). During 12-15 years of follow-up, there were 821 incident myocardial infarctions, 807 ischemic strokes, 161 hemorrhagic strokes, 159 venous thrombotic events, and 3413 participants died. Platelet count was not associated with the occurrence of myocardial infarction, ischemic or hemorrhagic stroke, venous thrombosis, or cardiovascular mortality. Non-cardiovascular mortality was higher among both participants with low and with high platelet count. Adjusted non-cardiovascular mortality rates for platelet counts below 100, 100-199, 300-399, and above 400 x 10(9) L(-1) relative to the reference mortality rate in participants with platelet count values between 200 and 299 x 10(9) L(-1) were 1.89 (1.21-2.96), 1.08 (0.98-1.20), 1.20 (1.06-1.37), and 1.47 (1.14-1.90), respectively. CONCLUSION: Platelet counts were not associated with vascular outcomes but low and high platelet counts were associated with non-cardiovascular mortality, including cancer mortality.
Keywords: Aged; Aged, 80 and over; Cause of Death; Cerebral Hemorrhage; Female; Humans; Male; Myocardial Infarction; Platelet Count; Risk; Stroke; Survival Analysis; Thrombosis; Venous Thrombosis

Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. - Winkelman, John W; Redline, Susan; Baldwin, Carol M; Resnick, Helaine E; Newman, Anne B; Gottlieb, Daniel J (Sleep, 2009)
STUDY OBJECTIVES: Sleep disturbance is the primary clinical morbidity of restless legs syndrome (RLS). To date, sleep disturbance in RLS has been measured in (1) clinical samples with polysomnography (PSG) or (2) population-based samples by self-report. The objective of this study was to analyze sleep by PSG in a population-based sample with symptoms of RLS. DESIGN: Cross-sectional observational study. SETTING: Community-based. PARTICIPANTS: 3433 older men and women. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: RLS was evaluated using an 8-item self-administered questionnaire based on NIH diagnostic criteria and required symptoms occurring > or = five times per month and associated with at least moderate distress. Health-related quality of life (HRQOL) was determined using the SF-36. Unattended, in-home PSG was performed. Data were assessed using general linear models with adjustment for demographic, health-related variables, and apnea-hypopnea index (AHI). Subjects with RLS had longer adjusted mean sleep latency (39.8 vs 26.4 min, P < 0.0001) and higher arousal index (20.1 vs 18.0, P = 0.0145) than those without RLS. Sleep latency increased progressively as the frequency of RLS symptoms increased from 5-15 days per month to 6-7 days per week. No differences in sleep stage percentages were observed between participants with and without RLS. Subjects with RLS also reported poorer HRQOL in all physical domains as well as in the Mental Health and Vitality domains. CONCLUSIONS: These novel PSG data from a nonclinical, community-based sample of individuals with RLS document sleep disturbance in the home even in individuals with intermittent symptoms.
Keywords: Adult; Aged; Cohort Studies; Comorbidity; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Polysomnography; Prospective Studies; Quality of Life; Restless Legs Syndrome; Sleep Initiation and Maintenance Disorders; Statistics as Topic

Predicting risk of dementia in older adults: The late-life dementia risk index. - Barnes, D E; Covinsky, K E; Whitmer, R A; Kuller, L H; Lopez, O L; Yaffe, K (Neurology, 2009)
OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.
Keywords: Age Factors; Aged; Aged, 80 and over; Alcohol Drinking; Apolipoprotein E4; Body Mass Index; Carotid Stenosis; Cerebrum; Cognition Disorders; Cohort Studies; Coronary Artery Bypass; Dementia; Female; Genetic Markers; Health Status Indicators; Humans; Logistic Models; Male; Predictive Value of Tests; Risk Assessment; Risk Factors; Risk Reduction Behavior

Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. - McGeechan, Kevin; Liew, Gerald; Macaskill, Petra; Irwig, Les; Klein, Ronald; Klein, Barbara E K; Wang, Jie Jin; Mitchell, Paul; Vingerling, Johannes R; de Jong, Paulus T V M; Witteman, Jacqueline C M; Breteler, Monique M B; et al. (Am J Epidemiol, 2009)
The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.
Keywords: Aged; Fluorescein Angiography; Humans; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Retinal Artery; Retinal Vein; Retinal Vessels; Risk Factors; Stroke

Prevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study. - Pratt, Sheila R; Kuller, Lewis; Talbott, Evelyn O; McHugh-Pemu, Kathleen; Buhari, Alhaji M; Xu, Xiaohui (J Speech Lang Hear Res, 2009)
PURPOSE: The goal of this study was to determine the impact of age, gender, and race on the prevalence and severity of hearing loss in elder adults, aged 72-96 years, after accounting for income, education, smoking, and clinical and subclinical cardiovascular disease. Methods Air-conduction thresholds for standard and extended high-frequency pure-tones were obtained from a cohort of 548 (out of 717) elderly adults (ages 72-96 years) who were recruited during the Year 11 clinical visit (1999-2000) of the Cardiovascular Health Study (CHS) at the Pittsburgh, Pennsylvania site. Participant smoking, income, education, and cardiovascular disease histories were obtained from the CHS database and were included as factors. RESULTS: Hearing loss was more common and more severe for the participants in their 80s than for those in their 70s-the men more than the women and the White participants more than the Black participants. The inclusion of education, income, smoking, and cardiovascular disease (clinical and subclinical) histories as factors did not substantively impact the overall results. CONCLUSION: Although the data reported in this article were cross-sectional and a cohort phenomenon might have been operational, they suggested that hearing loss is more substantive in the 8th than the 7th decade of life and that race and gender influence this decline in audition. Given the high prevalence in the aging population and the differences across groups, there is a clear need to understand the nature and causes of hearing loss across various groups in order to improve prevention and develop appropriate interventions.
Keywords: African Americans; Aged; Aged, 80 and over; Aging; Auditory Threshold; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; European Continental Ancestry Group; Female; Hearing Loss; Hearing Tests; Humans; Male; Occupations; Prevalence; Sex Characteristics; Smoking; Socioeconomic Factors; United States

Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. - O'Connor, George T; Caffo, Brian; Newman, Anne B; Quan, Stuart F; Rapoport, David M; Redline, Susan; Resnick, Helaine E; Samet, Jonathan; Shahar, Eyal (Am J Respir Crit Care Med, 2009)
RATIONALE: Cross-sectional epidemiologic studies show an association between sleep-disordered breathing and hypertension, but only one cohort study has examined sleep-disordered breathing as a risk factor for incident hypertension. OBJECTIVES: To examine whether sleep-disordered breathing increases the risk of incident hypertension among persons 40 years of age and older. METHODS: In a prospective cohort study, we analyzed data from 2,470 participants who at baseline did not have hypertension, defined as blood pressure of at least 140/90 mm Hg or taking antihypertensive medication. The apnea-hypopnea index (AHI), the number of apneas plus hypopneas per hour of sleep, was measured by overnight in-home polysomnography. We estimated odds ratios for developing hypertension during 5 years of follow-up according to baseline AHI. MEASUREMENTS AND MAIN RESULTS: The odds ratios for incident hypertension increased with increasing baseline AHI; however, this relationship was attenuated and not statistically significant after adjustment for baseline body-mass index. Although not statistically significant, the observed association between a baseline AHI greater than 30 and future hypertension (odds ratio, 1.51; 95% confidence interval, 0.93-2.47) does not exclude the possibility of a modest association. CONCLUSIONS: Among middle-aged and older persons without hypertension, much of the relationship between AHI and risk of incident hypertension was accounted for by obesity. After adjustment for body mass index, the AHI was not a significant predictor of future hypertension, although a modest influence of an AHI greater than 30 on hypertension could not be excluded.
Keywords: Adult; Blood Pressure; Confidence Intervals; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Odds Ratio; Polysomnography; Prognosis; Prospective Studies; Risk Factors; Sleep Apnea Syndromes; Time Factors; United States

Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study). - Parashar, Susmita; Katz, Ronit; Smith, Nicholas L; Arnold, Alice M; Vaccarino, Viola; Wenger, Nanette K; Gottdiener, John S (Am J Cardiol, 2009)
In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15% to 20% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.
Keywords: African Americans; Age Factors; Aged; Aged, 80 and over; Cohort Studies; Continental Population Groups; European Continental Ancestry Group; Female; Heart Failure; Humans; Incidence; Male; Proportional Hazards Models; Sex Factors; United States

Rapid decline of kidney function increases cardiovascular risk in the elderly. - Shlipak, Michael G; Katz, Ronit; Kestenbaum, Bryan; Siscovick, David; Fried, Linda; Newman, Anne; Rifkin, Dena; Sarnak, Mark J (J Am Soc Nephrol, 2009)
Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C-based estimated GFR as >3 ml/min per 1.73 m(2)/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95% CI 1.21 to 1.83), and PAD (HR 1.67; 95% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Heart Failure; Humans; Longitudinal Studies; Male; Myocardial Infarction; Peripheral Vascular Diseases; Renal Insufficiency, Chronic; Risk Factors; Stroke; Time Factors; United States

Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C. - Shlipak, Michael G; Katz, Ronit; Kestenbaum, Bryan; Fried, Linda F; Newman, Anne B; Siscovick, David S; Stevens, Lesley; Sarnak, Mark J (Am J Nephrol, 2009)
BACKGROUND/AIMS: The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C. METHODS: In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 +/- 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m(2)). RESULTS: Mean annual eGFR loss as estimated from creatinine was 0.4 +/- 3.6 ml/min/1.73 m(2), with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 +/- 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16-1.65), 1.62 (1.31-1.99) and 2.96 (2.28-3.84) for participants aged 70-74, 75-79 and 80+ at baseline, compared with those aged 65-69. CONCLUSION: In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.
Keywords: Age Factors; Aged; Creatinine; Cystatin C; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Risk Factors

Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis. - Smith, N L; Wiggins, K L; Reiner, A P; Lange, L A; Cushman, M; Heckbert, S R; Lumley, T; Rice, K M; Folsom, A R; Psaty, B M (J Thromb Haemost, 2009)
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Hemostasis; Humans; Incidence; Male; Menopause; Middle Aged; Polymorphism, Single Nucleotide; Reproducibility of Results; Risk; Thrombophilia; Venous Thrombosis; Young Adult

Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study. - Yanez, N David; Burke, Gregory L; Manolio, Teri; Gardin, Julius M; Polak, Joseph (Ann Epidemiol, 2009)
PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults. METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups. RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile. CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.
Keywords: Aged; Atherosclerosis; Female; Genetic Predisposition to Disease; Humans; Incidence; Male; Myocardial Infarction; Odds Ratio; Prevalence; Prospective Studies; Risk Factors; Siblings; Stroke; United States

Sleep-disordered breathing and frailty in the Cardiovascular Health Study Cohort. - Endeshaw, Yohannes W; Unruh, Mark L; Kutner, Michael; Newman, Anne B; Bliwise, Donald L (Am J Epidemiol, 2009)
Sleep-disordered breathing (SDB) is associated with pathophysiology that may influence the development and progression of frailty. Using data collected in 1995-1996, the authors explored the relation between SDB and components of frailty among 1,042 participants of the Cardiovascular Health Study. Diagnosis of SDB was based on the results of overnight polysomnography, and severe SDB was defined as an apnea-hypopnea index of >30 per hour of sleep. Slow walking speed, low grip strength, exhaustion, low physical activity, and unexplained weight loss were referred to as frailty indicator variables. There were 584 (56%) female and 458 (44%) male participants, and the mean age was 77 (standard deviation, 4) years. There was independent association between severe SDB and 1 or more frailty indicator variables (adjusted odds ratio = 4.85, 95% confidence interval: 1.40, 16.78), slow walking speed (adjusted odds ratio = 2.67, 95% confidence interval: 1.04, 6.84), and low grip strength (adjusted odds ratio = 3.29, 95% confidence interval: 1.36, 7.96) among female study participants. The finding of an independent association between SDB and frailty indicator variables among older women could have important implications in interventions aimed at preventing or delaying the progression of frailty.
Keywords: Activities of Daily Living; Aged; Cardiovascular Diseases; Cardiovascular System; Cohort Studies; Confidence Intervals; Exercise Tolerance; Female; Frail Elderly; Hand Strength; Humans; Logistic Models; Male; Mobility Limitation; Models, Statistical; Motor Activity; Muscle Strength; Odds Ratio; Polysomnography; Psychometrics; Risk Factors; Sleep Apnea, Obstructive; Weight Loss

Sleep-disordered breathing and mortality: a prospective cohort study. - Punjabi, Naresh M; Caffo, Brian S; Goodwin, James L; Gottlieb, Daniel J; Newman, Anne B; O'Connor, George T; Rapoport, David M; Redline, Susan; Resnick, Helaine E; Robbins, John A; Shahar, Eyal; Unruh, Mark L; et al. (PLoS Med, 2009)
BACKGROUND: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older. METHODS AND FINDINGS: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea-hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0-14.9 events/h), moderate (AHI: 15.0-29.9 events/h), and severe (AHI: >or=30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80-1.08), 1.17 (95% CI: 0.97-1.42), and 1.46 (95% CI: 1.14-1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40-70 y (hazard ratio: 2.09; 95% CI: 1.31-3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease-related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality. CONCLUSIONS: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40-70 y with severe sleep-disordered breathing. Please see later in the article for the Editors' Summary.
Keywords: Aged; Coronary Artery Disease; Female; Humans; Hypoxia; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors; Sleep Apnea Syndromes; Survival Analysis

Spousal suffering and partner's depression and cardiovascular disease: the Cardiovascular Health Study. - Schulz, Richard; Beach, Scott R; Hebert, Randy S; Martire, Lynn M; Monin, Joan K; Tompkins, Connie A; Albert, Steven M (Am J Geriatr Psychiatry, 2009)
OBJECTIVES: To assess the effects of suffering in a spouse on prevalent and incident psychiatric (depression) and physical morbidity (cardiovascular disease [CVD]) in their partner, controlling for known risk factors for depression and CVD. DESIGN: Descriptive longitudinal study. PARTICIPANTS: A total of 1,330 older married couples enrolled in the Cardiovascular Health Study, a large epidemiologic study of the elderly. MEASUREMENTS: Predictor variables were physical, psychological, and existential/spiritual indicators of suffering. Primary outcomes were prevalent and incident depression and CVD. RESULTS: Controlling for known risk factors for depression, the authors found a dose-response relationship between suffering in a spouse and concurrent depression in their partner as well as a relationship between suffering and the partner's future risk for depression. With respect to CVD, and controlling for subclinical CVD at baseline, husbands whose wives reported high levels of suffering also had higher rates of prevalent CVD, but there were no significant associations between wives suffering and husbands incident CVD. There were no associations between husbands' suffering and wives' prevalent or incident CVD. CONCLUSION: Exposure to spousal suffering is an independent and unique source of distress in married couples that contributes to psychiatric and physical morbidity. More attention should be paid to the interpersonal effects of suffering in married couples and to its role in contributing to morbidity.
Keywords: Activities of Daily Living; Aged; Cardiovascular Diseases; Caregivers; Depression; Female; Follow-Up Studies; Humans; Incidence; Logistic Models; Longitudinal Studies; Male; Prevalence; Risk Factors; Socioeconomic Factors; Spouses; Stress, Psychological; Surveys and Questionnaires

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. - Jackson, Dan; White, Ian; Kostis, J B; Wilson, A C; Folsom, A R; Wu, K; Chambless, L; Benderly, M; Goldbourt, U; Willeit, J; Kiechl, S; Yarnell, J W G; et al. (Stat Med, 2009)
One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts
Keywords: Cohort Studies; Computer Simulation; Coronary Disease; Data Interpretation, Statistical; Female; Fibrinogen; Humans; Male; Meta-Analysis as Topic; Models, Statistical

Total and cause-specific mortality in the cardiovascular health study. - Newman, Anne B; Sachs, Michael C; Arnold, Alice M; Fried, Linda P; Kronmal, Richard; Cushman, Mary; Psaty, Bruce M; Harris, Tamara B; Robbins, John A; Burke, Gregory L; Kuller, Lewis H; Lumley, Thomas (J Gerontol A Biol Sci Med Sci, 2009)
BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity. METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models. RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death. CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cause of Death; Chronic Disease; Cohort Studies; Female; Geriatric Assessment; Health Surveys; Humans; Kaplan-Meier Estimate; Male; Probability; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; United States

Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study. - Cappola, Anne R; O'Meara, Ellen S; Guo, Wensheng; Bartz, Traci M; Fried, Linda P; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2009)
BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual's ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging. METHODS: Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points. RESULTS: Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001). CONCLUSIONS: Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Cardiovascular Diseases; Cause of Death; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Geriatric Assessment; Humans; Longitudinal Studies; Male; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; United States

Usefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure. - Tang, W H Wilson; Katz, Ronit; Brennan, Marie-Luise; Aviles, Ronnier J; Tracy, Russell P; Psaty, Bruce M; Hazen, Stanley L (Am J Cardiol, 2009)
Increased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 +/- 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (<or=75 years old, systolic blood pressure <or=136 mm Hg, no subclinical cardiovascular disease, and no diabetes mellitus). In conclusion, an independent association between increased MPO and the development of HF in apparently healthy elderly subjects was observed, particularly beyond MI and traditional cardiac risk factors.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Geriatric Assessment; Heart Failure; Humans; Longitudinal Studies; Male; Peroxidase; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors

Using telephone and informant assessments to estimate missing Modified Mini-Mental State Exam scores and rates of cognitive decline. The cardiovascular health study. - Arnold, Alice M; Newman, Anne B; Dermond, Norma; Haan, Mary; Fitzpatrick, Annette (Neuroepidemiology, 2009)
AIM: To estimate an equivalent to the Modified Mini-Mental State Exam (3MSE), and to compare changes in the 3MSE with and without the estimated scores. METHODS: Comparability study on a subset of 405 participants, aged >or=70 years, from the Cardiovascular Health Study (CHS), a longitudinal study in 4 United States communities. The 3MSE, the Telephone Interview for Cognitive Status (TICS) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were administered within 30 days of one another. Regression models were developed to predict the 3MSE score from the TICS and/or IQCODE, and the predicted values were used to estimate missing 3MSE scores in longitudinal follow-up of 4,274 CHS participants. RESULTS: The TICS explained 67% of the variability in 3MSE scores, with a correlation of 0.82 between predicted and observed scores. The IQCODE alone was not a good estimate of 3MSE score, but improved the model fit when added to the TICS model. Using estimated 3MSE scores classified more participants with low cognition, and rates of decline were greater than when only the observed 3MSE scores were considered. CONCLUSIONS: 3MSE scores can be reliably estimated from the TICS, with or without the IQCODE. Incorporating these estimates captured more cognitive decline in older adults.
Keywords: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cognition Disorders; Female; Humans; Interviews as Topic; Longitudinal Studies; Male; Predictive Value of Tests; Psychiatric Status Rating Scales; Regression Analysis; Risk Factors; ROC Curve; United States

Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. - Benjamin, Emelia J; Rice, Kenneth M; Arking, Dan E; Pfeufer, Arne; van Noord, Charlotte; Smith, Albert V; Schnabel, Renate B; Bis, Joshua C; Boerwinkle, Eric; Sinner, Moritz F; Dehghan, Abbas; Lubitz, Steven A; et al. (Nat Genet, 2009)
We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).
Keywords: Atrial Fibrillation; Chromosomes, Human, Pair 16; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeodomain Proteins; Humans; Meta-Analysis as Topic; Mutation; Polymorphism, Single Nucleotide; Reproducibility of Results

Admixture mapping of ankle-arm index: identification of a candidate locus associated with peripheral arterial disease. - Scherer, M L; Nalls, M A; Pawlikowska, L; Ziv, E; Mitchell, G; Huntsman, S; Hu, D; Sutton-Tyrrell, K; Lakatta, E G; Hsueh, W-C; Newman, A B; Tandon, A; et al. (J Med Genet, 2010)
BACKGROUND: Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle-arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD. METHODS: The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus. RESULTS: The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95% CI 1.29 to 2.76). CONCLUSION: This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans.
Keywords: African Americans; Aged; Ankle Brachial Index; Chromosome Mapping; Chromosomes, Human, Pair 11; Female; Genetic Loci; Genotype; Humans; Male; Odds Ratio; Peripheral Vascular Diseases; Polymorphism, Single Nucleotide

Age and cystatin C in healthy adults: a collaborative study. - Odden, Michelle C; Tager, Ira B; Gansevoort, Ron T; Bakker, Stephan J L; Katz, Ronit; Fried, Linda F; Newman, Anne B; Canada, Robert B; Harris, Tamara; Sarnak, Mark J; Siscovick, David; Shlipak, Michael G (Nephrol Dial Transplant, 2010)
BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum. METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction). CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.
Keywords: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Cystatin C; Humans; Kidney; Middle Aged; Reference Values

Albuminuria and the risk of incident stroke and stroke types in older adults. - Aguilar, M I; O'Meara, E S; Seliger, S; Longstreth, W T; Hart, R G; Pergola, P E; Shlipak, M G; Katz, R; Sarnak, M J; Rifkin, D E (Neurology, 2010)
BACKGROUND: The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate. METHODS: These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006. RESULTS: A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47-3.00), while HR for eGFR was 1.29 (95% CI 0.91-1.84) and for cystatin C was 1.22 (95% CI 0.85-1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories. CONCLUSIONS: UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.
Keywords: Aged; Aged, 80 and over; Albuminuria; Community Health Services; Confidence Intervals; Female; Geriatric Assessment; Glomerular Filtration Rate; Humans; Incidence; Longitudinal Studies; Male; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stroke

Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. - Rifkin, Dena E; Katz, Ronit; Chonchol, Michel; Fried, Linda F; Cao, Jie; de Boer, Ian H; Siscovick, David S; Shlipak, Michael G; Sarnak, Mark J (Nephrol Dial Transplant, 2010)
BACKGROUND: Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known. METHODS: We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m(2)); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m(2)); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m(2)). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure. RESULTS: One thousand one hundred fifty (34.9%) had normal kidney function (12.2% with MA), 1518 (46.1%) had preclinical kidney disease (17.9% with MA) and 622 (18.9%) had CKD (47% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk. CONCLUSION: Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.
Keywords: Aged; Albuminuria; Cardiovascular Diseases; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Heart Failure; Humans; Male; Myocardial Infarction; Risk Factors

Alcohol consumption and kidney function decline in the elderly: alcohol and kidney disease. - Menon, Vandana; Katz, Ronit; Mukamal, Kenneth; Kestenbaum, Bryan; de Boer, Ian H; Siscovick, David S; Sarnak, Mark J; Shlipak, Michael G (Nephrol Dial Transplant, 2010)
BACKGROUND: Alcohol consumption appears to be protective for cardiovascular disease; however, its relationship with kidney disease is unclear. METHODS: This prospective cohort study included 4343 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged ≥65 from four US communities. We used previously defined categories based on weekly alcohol consumption: none, former, <1 drink, 1-6 drinks, 7-13 drinks and ≥14 drinks. Cystatin C was measured at baseline, year 3 and year 7; eligible subjects had at least two measures. Estimated GFR(cys) was calculated from cystatin C. The primary outcome was rapid kidney function as an annual estimated GFR (eGFR(cys)) loss >3 mL/min/1.73 m(2)/year. RESULTS: Eight percent of the cohort reported former alcohol use and 52% reported current alcohol consumption. During a mean follow-up of 5.6 years, 1075 (25%) participants had rapid kidney function decline. In adjusted logistic regression models, there was no association between alcohol use and kidney function decline (odds ratio, 95% confidence interval: none = reference; former = 1.18, 0.89-1.56; <1 drink = 1.20, 0.99-1.47; 1-6 = 1.18, 0.95-1.45; 7-13 = 1.10, 0.80-1.53; >14 = 0.89, 0.61-1.13). Results were similar with kidney function decline as a continuous outcome. CONCLUSIONS: Our results suggest that moderate alcohol consumption has neither adverse nor beneficial effects on kidney function. Although clinicians will need to consider the potential deleterious effects associated with alcohol consumption, there does not appear to be a basis for recommending that older adults discontinue or initiate light to moderate alcohol consumption to protect against kidney disease.
Keywords: Aged; Aging; Alcohol Drinking; Cohort Studies; Cystatin C; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Prospective Studies

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. - Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I; Monda, Keri L; Thorleifsson, Gudmar; Jackson, Anne U; Lango Allen, Hana; Lindgren, Cecilia M; Luan, Jian'an; Mägi, Reedik; Randall, Joshua C; Vedantam, Sailaja; et al. (Nat Genet, 2010)
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Keywords: Body Height; Body Mass Index; Body Size; Body Weight; Chromosome Mapping; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Obesity; Polymorphism, Single Nucleotide

Association between adiposity in midlife and older age and risk of diabetes in older adults. - Biggs, Mary L; Mukamal, Kenneth J; Luchsinger, José A; Ix, Joachim H; Carnethon, Mercedes R; Newman, Anne B; de Boer, Ian H; Strotmeyer, Elsa S; Mozaffarian, Dariush; Siscovick, David S (JAMA, 2010)
CONTEXT: Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults. OBJECTIVE: To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later. MAIN OUTCOME MEASURE: Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater. RESULTS: Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+/-2 kg), those who gained the most weight from 50 years of age to baseline (> or = 9 kg), and from baseline to the third follow-up visit (> or = 6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less. CONCLUSION: Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
Keywords: Adiposity; Age Factors; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Male; Prospective Studies; Risk Factors; United States; Weight Gain

Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. - Rifkin, Dena E; Katz, Ronit; Fried, Linda F; Kestenbaum, Bryan; Jenny, Nancy Swords; Newman, Anne B; Siscovick, David S; Shlipak, Michael G; Sarnak, Mark J (Nephron Clin Pract, 2010)
BACKGROUND: In cross-sectional analyses, C-reactive protein (CRP) levels are inversely related to levels of kidney function. The relationship between kidney function and subsequent changes in CRP is unknown. METHODS: We studied 4,364 individuals from the Cardiovascular Health Study, a longitudinal cohort of community-dwelling older adults. Baseline eGFRcys was estimated using cystatin C. CRP was measured at baseline and after 3 and 7 years of follow-up; slopes of change in CRP were calculated. RESULTS: The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m(2). The median (interquartile range IQR) baseline CRP was 2.39 (1.22, 4.33) mg/l; the median (IQR) yearly change in CRP was -0.0051 (-0.020 to 0.27) mg/l/year. After adjustment for demographic characteristics and the initial level of CRP, each standard deviation lower baseline eGFR was associated with a small and non-significant yearly increase in CRP (0.032 mg/l/year; 95% CI: -0.005 to 0.070, p = 0.094). CONCLUSIONS: We did not find a relationship between eGFR and subsequent changes in CRP. The association between kidney function and CRP in cross-sectional analyses may reflect unmeasured confounding by atherosclerosis; alternatively, the burden of comorbidity and interval mortality in this population may have masked a stronger longitudinal association between kidney function and change in CRP. Further study in younger populations may clarify whether impaired kidney function leads to change in inflammation over time.
Keywords: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Function Tests; Longitudinal Studies; Male; Residence Characteristics

Association between depressive symptoms and fibrosis markers: the Cardiovascular Health Study. - Kop, Willem J; Kuhl, Emily A; Barasch, Eddy; Jenny, Nancy S; Gottlieb, Stephen S; Gottdiener, John S (Brain Behav Immun, 2010)
OBJECTIVE: Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above. METHODS: Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9+/-5.9 yrs, 49% women) using a case-control design based on heart failure status (307 HF patients and 563 age- and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D > or = 8). Covariates included demographic and clinical variables. RESULTS: Depression was associated with higher levels of PIP (median=411.0, inter-quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, IQR=3.53-6.85 vs. 4.53, IQR=3.26-6.22 microg/L, p=0.024), but not PIIIINP (4.07, IQR=2.75-5.54 microg/L vs. 3.58, IQR=2.71-5.01 microg/L, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers. CONCLUSIONS: Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.
Keywords: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Collagen Type I; Depression; Electrocardiography; Endomyocardial Fibrosis; Fatigue; Female; Fibrosis; Health Surveys; Heart Failure; Humans; Inflammation Mediators; Male; Multivariate Analysis; Peptide Fragments; Procollagen; Psychiatric Status Rating Scales; Risk Factors; Socioeconomic Factors

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. - Smith, Nicholas L; Felix, Janine F; Morrison, Alanna C; Demissie, Serkalem; Glazer, Nicole L; Loehr, Laura R; Cupples, L Adrienne; Dehghan, Abbas; Lumley, Thomas; Rosamond, Wayne D; Lieb, Wolfgang; Rivadeneira, Fernando; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3. CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
Keywords: African Americans; Aged; Aged, 80 and over; Cohort Studies; Endopeptidases; European Continental Ancestry Group; Female; Genome-Wide Association Study; Heart Failure; Humans; Incidence; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk; Ubiquitin-Specific Proteases

Association of Holter-based measures including T-wave alternans with risk of sudden cardiac death in the community-dwelling elderly: the Cardiovascular Health Study. - Stein, Phyllis K; Sanghavi, Devang; Sotoodehnia, Nona; Siscovick, David S; Gottdiener, John (J Electrocardiol, 2010)
BACKGROUND: Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher/lower risk is critical. METHODS: The Cardiovascular Health Study is a population-based study of risk factors for coronary heart disease and stroke those 65 years or older. Forty-nine (of 1649) with usable Holters and in normal sinus rhythm had SCD during follow-up and were matched with 2 controls, alive at the time of death of the case and not experiencing SCD on follow-up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD. RESULTS: In univariate models, the upper half of ventricular premature contraction (VPC) counts, abnormal heart rate turbulence, decreased normalized low-frequency power, increased T-wave alternans (TWA), and decreased the short-term fractal scaling exponent (DFA(1)) were associated with SCD, but time domain heart rate variability was not. In multivariate models, the upper half of VPC counts (odds ratio [OR], 6.6) and having TWA of 37 muV or greater on channel 2 (OR, 4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR, 6.9) and having a DFA(1) of less than 1.05 (OR, 5.0) were independently associated with SCD. When additive effects were explored, having both higher VPCs and higher TWA was associated with an OR of 8.2 for SCD compared with 2.6 for having either. Also, having both higher VPCs and lower DFA(1) was associated with an OR of 9.6 for SCD compared with 3.1 for having either. CONCLUSIONS: Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.
Keywords: Comorbidity; Coronary Artery Disease; Death, Sudden, Cardiac; Electrocardiography, Ambulatory; Female; Humans; Male; Prevalence; Prognosis; Reproducibility of Results; Risk Assessment; Risk Factors; Sensitivity and Specificity; Survival Analysis; Survival Rate; United States; Ventricular Premature Complexes

Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. - deFilippi, Christopher R; de Lemos, James A; Christenson, Robert H; Gottdiener, John S; Kop, Willem J; Zhan, Min; Seliger, Stephen L (JAMA, 2010)
CONTEXT: Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death. OBJECTIVES: To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918). MAIN OUTCOME MEASURES: New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors. RESULTS: Cardiac troponin T was detectable (≥3.00 pg/mL) in 2794 participants (66.2%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95% CI, 4.3-5.4; aHR, 2.91; 95% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95% CI, 1.4-1.8 and 1.1; 95% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50% (n = 393, 22%) was associated with a greater risk for HF (aHR, 1.61; 95% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95% CI, 1.35-2.03) and a decrease of more than 50% (n = 247, 14%) was associated with a lower risk for HF (aHR, 0.73; 95% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95% CI, 0.52-0.97) compared with participants with 50% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death. CONCLUSION: In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.
Keywords: Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Female; Heart Failure; Humans; Incidence; Male; Predictive Value of Tests; Risk; Sensitivity and Specificity; Troponin T; United States

Associations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study. - Pearce, Jeffrey D; Craven, Timothy E; Edwards, Matthew S; Corriere, Matthew A; Crutchley, Teresa A; Fleming, Shawn H; Hansen, Kimberley J (Am J Kidney Dis, 2010)
BACKGROUND: Atherosclerotic renovascular disease is associated with an increased risk of cardiovascular disease (CVD) events. This study examines associations between Doppler-derived parameters from the renal artery and renal parenchyma and all-cause mortality and fatal and nonfatal CVD events in a cohort of elderly Americans. STUDY DESIGN: Cohort study. SETTING: A subset of participants from the Cardiovascular Health Study (CHS). Through an ancillary study, 870 (70% recruitment) Forsyth County, NC, CHS participants consented to undergo renal duplex sonography to define the prevalence of renovascular disease in the elderly, resulting in 726 (36% men; mean age, 77 years) technically adequate complete studies included in this investigation. PREDICTOR: Renal duplex sonography-derived Doppler signals from the main renal arteries and renal parenchyma. Spectral analysis from Doppler-shifted frequencies and angle of insonation were used to estimate renal artery peak systolic and end diastolic velocity (both in meters per second). Color Doppler was used to identify the corticomedullary junction. Using a 3-mm Doppler sample, the parenchymal peak systolic and end diastolic frequency shift (both in kilohertz) were obtained. Resistive index was calculated as (1 - [end diastolic frequency shift/peak systolic frequency shift]) using Doppler samples from the hilar arteries of the left or right kidney with the higher main renal artery peak systolic velocity. OUTCOMES & MEASUREMENTS: Proportional hazard regression analysis was used to determine associations between renal duplex sonography-derived Doppler signals and CVD events and all-cause mortality adjusted for accepted cardiovascular risk factors. Index CVD outcomes were defined as coronary events (angina, myocardial infarction, and coronary artery bypass grafting/percutaneous coronary intervention), cerebrovascular events (stroke or transient ischemic attack), and any CVD event (angina, congestive heart failure, myocardial infarction, stroke, transient ischemic attack, and coronary artery bypass grafting [CABG]/percutaneous transluminal coronary intervention [PTCI]). RESULTS: During follow-up, 221 deaths (31%), 229 CVD events (32%), 122 coronary events (17%), and 92 cerebrovascular events (13%) were observed. Renal duplex sonography-derived Doppler signals from the renal parenchyma were associated independently with all-cause mortality and CVD outcomes. In particular, increased parenchymal end diastolic frequency shift was associated significantly with any CVD event (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001). Marginally significant associations were observed between increases in parenchymal end diastolic frequency shift and decreased risk of death (HR, 0.86; 95% CI, 0.73-1.00; P = 0.06) and decreased risk of cerebrovascular events (HR, 0.78; 95% CI, 0.61-1.01; P = 0.06). Parenchymal end diastolic frequency shift was not significantly predictive of coronary events (HR, 0.84; 95% CI, 0.67-1.06; P = 0.1). LIMITATIONS: CHS participants showed a "healthy cohort" effect that may underestimate the rate of CVD events in the general population. CONCLUSION: Renal duplex sonographic Doppler signals from the renal parenchyma showed significant associations with subsequent CVD events after controlling for other significant risk factors. In particular, a standard deviation increase in parenchymal end diastolic frequency shift was associated with 27% risk reduction in any CVD event.
Keywords: Aged; Cardiovascular Diseases; Cohort Studies; Female; Humans; Kidney Diseases; Male; Renal Artery; Risk Factors; Ultrasonography, Doppler, Duplex

Associations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas. - Zanobetti, Antonella; Redline, Susan; Schwartz, Joel; Rosen, Dennis; Patel, Sanjay; O'Connor, George T; Lebowitz, Michael; Coull, Brent A; Gold, Diane R (Am J Respir Crit Care Med, 2010)
RATIONALE: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood. OBJECTIVES: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM(10)) was associated with SDB among persons 39 years of age and older. METHODS: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O(2) saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM(10) and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects). MEASUREMENTS AND MAIN RESULTS: In summer, increases in RDI or percentage of sleep time at less than 90% O(2) saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM(10). Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature. CONCLUSIONS: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.
Keywords: Adult; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Cities; Cohort Studies; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Particle Size; Particulate Matter; Polysomnography; Seasons; Severity of Illness Index; Sleep; Sleep Apnea Syndromes; Temperature; United States; Urban Health

Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. - Kop, Willem J; Stein, Phyllis K; Tracy, Russell P; Barzilay, Joshua I; Schulz, Richard; Gottdiener, John S (Psychosom Med, 2010)
OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression. METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 ± 4.6 years; 59.1% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates. RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7% (p < .001). CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.
Keywords: Aged; Autonomic Nervous System Diseases; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cause of Death; Cohort Studies; Comorbidity; Depressive Disorder; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Inflammation; Interleukin-6; Leukocyte Count; Male; Risk Factors

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables. - Burgess, Stephen; Thompson, Simon G; Burgess, S; Thompson, S G; Andrews, G; Samani, N J; Hall, A; Whincup, P; Morris, R; Lawlor, D A; Davey Smith, G; Timpson, N; et al. (Stat Med, 2010)
Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.
Keywords: Bayes Theorem; Biostatistics; C-Reactive Protein; Fibrinogen; Genetic Markers; Humans; Meta-Analysis as Topic; Models, Statistical; Phenotype; Polymorphism, Single Nucleotide

Biological, clinical and population relevance of 95 loci for blood lipids. - Teslovich, Tanya M; Musunuru, Kiran; Smith, Albert V; Edmondson, Andrew C; Stylianou, Ioannis M; Koseki, Masahiro; Pirruccello, James P; Ripatti, Samuli; Chasman, Daniel I; Willer, Cristen J; Johansen, Christopher T; Fouchier, Sigrid W; et al. (Nature, 2010)
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Keywords: African Americans; Animals; Asian Continental Ancestry Group; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Europe; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Lipid Metabolism; Lipids; Liver; Male; Mice; N-Acetylgalactosaminyltransferases; Phenotype; Polymorphism, Single Nucleotide; Protein Phosphatase 1; Reproducibility of Results; Triglycerides

Body weight dynamics and their association with physical function and mortality in older adults: the Cardiovascular Health Study. - Arnold, Alice M; Newman, Anne B; Cushman, Mary; Ding, Jingzhong; Kritchevsky, Stephen (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: To estimate the associations of weight dynamics with physical functioning and mortality in older adults. METHODS: Longitudinal cohort study using prospectively collected data on weight, physical function, and health status in four U.S. Communities in the Cardiovascular Health Study. Included were 3,278 participants (2,013 women and 541 African Americans), aged 65 or older at enrollment, who had at least five weight measurements. Weight was measured at annual clinic visits between 1992 and 1999, and summary measures of mean weight, coefficient of variation, average annual weight change, and episodes of loss and gain (cycling) were calculated. Participants were followed from 1999 to 2006 for activities of daily living (ADL) difficulty, incident mobility limitations, and mortality. RESULTS: Higher mean weight, weight variability, and weight cycling increased the risk of new onset of ADL difficulties and mobility limitations. After adjustment for risk factors, the hazard ratio (95% confidence interval) for weight cycling for incident ADL impairment was 1.28 (1.12, 1.47), similar to that for several comorbidities in our model, including cancer and diabetes. Lower weight, weight loss, higher variability, and weight cycling were all risk factors for mortality, after adjustment for demographic risk factors, height, self-report health status, and comorbidities. CONCLUSIONS: Variations in weight are important indicators of future physical limitations and mortality in the elderly and may reflect difficulties in maintaining homeostasis throughout older ages. Monitoring the weight of an older person for fluctuations or episodes of both loss and gain is an important aspect of geriatric care.
Keywords: Activities of Daily Living; Age Factors; Aged, 80 and over; Body Weight; Cardiovascular Diseases; Female; Follow-Up Studies; Health Status; Humans; Longevity; Male; Prospective Studies; Risk Factors; Survival Rate; United States

Brain structure and obesity. - Raji, Cyrus A; Ho, April J; Parikshak, Neelroop N; Becker, James T; Lopez, Oscar L; Kuller, Lewis H; Hua, Xue; Leow, Alex D; Toga, Arthur W; Thompson, Paul M (Hum Brain Mapp, 2010)
Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.
Keywords: Age Factors; Aged; Analysis of Variance; Body Mass Index; Brain; Continental Population Groups; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Obesity; Organ Size; Regression Analysis; Sex Factors

Cancer linked to Alzheimer disease but not vascular dementia. - Roe, C M; Fitzpatrick, A L; Xiong, C; Sieh, W; Kuller, L; Miller, J P; Williams, M M; Kopan, R; Behrens, M I; Morris, J C (Neurology, 2010)
OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Dementia, Vascular; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Hospitalization; Humans; Male; Neoplasms; Nerve Degeneration; Parkinson Disease; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors

Candidate gene association resource (CARe): design, methods, and proof of concept. - Musunuru, Kiran; Lettre, Guillaume; Young, Taylor; Farlow, Deborah N; Pirruccello, James P; Ejebe, Kenechi G; Keating, Brendan J; Yang, Qiong; Chen, Ming-Huei; Lapchyk, Nina; Crenshaw, Andrew; Ziaugra, Liuda; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
Keywords: African Americans; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Databases, Genetic; European Continental Ancestry Group; Genetic Association Studies; Genotype; Humans; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Research Design; Triglycerides

Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study. - Sanders, Jason L; Boudreau, Robert M; Cappola, Anne R; Arnold, Alice M; Robbins, John; Cushman, Mary; Newman, Anne B (J Am Geriatr Soc, 2010)
OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age. DESIGN: Longitudinal cohort study. SETTING: Pittsburgh, Pennsylvania. PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American). MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change. RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05). CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
Keywords: Age Distribution; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Humans; Longitudinal Studies; Male; Multivariate Analysis; Regression Analysis; Sex Distribution; United States

Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study. - Kizer, Jorge R; Arnold, Alice M; Strotmeyer, Elsa S; Ives, Diane G; Cushman, Mary; Ding, Jingzhong; Kritchevsky, Stephen B; Chaves, Paulo H M; Hirsch, Calvin H; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated. METHODS: We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996-1997 and 2005-2006, had serial adiponectin measurements and underwent follow-up through June 2009. RESULTS: Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95% confidence interval = 1.36-2.52 per SD ≥ 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95% confidence interval = 1.10-1.52 per SD). CONCLUSIONS: Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group.
Keywords: Adiponectin; Age Factors; Aged; Aging; Analysis of Variance; Cardiovascular Diseases; Cause of Death; Chi-Square Distribution; Cohort Studies; Cross-Sectional Studies; Female; Health Status; Humans; Linear Models; Male; Physical Fitness; Proportional Hazards Models; Risk Factors; Sex Factors; Time Factors; United States

Chronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study. - Whitson, Heather E; Landerman, Lawrence R; Newman, Anne B; Fried, Linda P; Pieper, Carl F; Cohen, Harvey Jay (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Older women experience disability more commonly than their male peers. This disparity may be due, in part, to sex-based differences in the prevalence or the disabling effects of common medical conditions. The objectives of this analysis were to (a) quantify the extent to which excess disability in women is explained by higher prevalence of selected medical conditions and (b) evaluate whether the same conditions have differing effects on disability in men and women. METHODS: We analyzed cross-sectional data from 5,888 community-dwelling older men and women. Disability was defined as difficulty with greater than or equal to one activity of daily living. Thirteen medical conditions were assessed by self-report, testing, or record review. RESULTS: Controlling for age, race, education, and marital status, women were more likely to experience disability (odds ratio = 1.70, 95% confidence interval = 1.36-2.11). Higher prevalence of arthritis and obesity in women explained 30.2% and 12.9%, respectively, of the sex-based difference in disability rates, whereas male prevalent diseases like vascular conditions and emphysema narrowed the disability gap. Women with arthritis, hearing problems, coronary artery disease, congestive heart failure, stroke, and claudication were more likely to exhibit disability compared with men with the same conditions (p < .001). CONCLUSIONS: Efforts to lessen sex-based inequality in disability should focus on reducing the prevalence of arthritis and obesity. Future generations may see greater functional disparity if rates of vascular disease and emphysema rise among women. Several conditions were more often associated with disability in women, suggesting additional sex-based differences in the disablement process.
Keywords: Aged; Arthritis; Cardiovascular Diseases; Chronic Disease; Cohort Studies; Comorbidity; Cross-Sectional Studies; Disabled Persons; Emphysema; Female; Hearing Disorders; Humans; Male; Obesity; Prevalence; Sex Distribution

Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. - Mozaffarian, Dariush; Cao, Haiming; King, Irena B; Lemaitre, Rozenn N; Song, Xiaoling; Siscovick, David S; Hotamisligil, Gökhan S (Am J Clin Nutr, 2010)
BACKGROUND: Animal experiments suggest that circulating palmitoleic acid (cis-16:1n-7) from adipocyte de novo fatty acid synthesis may directly regulate insulin resistance and metabolic dysregulation. OBJECTIVE: We investigated the independent determinants of circulating palmitoleate in free-living humans and whether palmitoleate is related to lower metabolic risk and the incidence of diabetes. DESIGN: In a prospective cohort of 3630 US men and women in the Cardiovascular Health Study, plasma phospholipid fatty acids, anthropometric variables, blood lipids, inflammatory markers, and glucose and insulin concentrations were measured between 1992 and 2006 by using standardized methods. Independent determinants of plasma phospholipid palmitoleate and relations of palmitoleate with metabolic risk factors were investigated by using multivariable-adjusted linear regression. Relations with incident diabetes (296 incident cases) were investigated by using Cox proportional hazards. RESULTS: The mean (± SD) palmitoleate value was 0.49 ± 0.20% (range: 0.11-2.55%) of total fatty acids. Greater body mass index, carbohydrate intake, protein intake, and alcohol use were each independent lifestyle correlates of higher palmitoleate concentrations. In multivariable analyses that adjusted for these factors and other potential confounders, higher palmitoleate concentrations were independently associated with lower LDL cholesterol (P < 0.001), higher HDL cholesterol (P < 0.001), lower total:HDL-cholesterol ratio (P = 0.04), and lower fibrinogen (P < 0.001). However, palmitoleate was also associated with higher triglycerides (P < 0.001) and (in men only) with greater insulin resistance (P < 0.001). Palmitoleate was not significantly associated with incident diabetes. CONCLUSIONS: Adiposity (energy imbalance), carbohydrate consumption, and alcohol use-even within typical ranges-are associated with higher circulating palmitoleate concentrations. Circulating palmitoleate is robustly associated with multiple metabolic risk factors but in mixed directions, perhaps related to divergent lifestyle determinants or endogenous sources (liver, adipose tissue) of fatty acid synthesis.
Keywords: Aged; Aged, 80 and over; Alcohol Drinking; Body Mass Index; Cholesterol; Cholesterol, HDL; Diabetes Mellitus; Diet; Dietary Carbohydrates; Fatty Acids, Monounsaturated; Female; Fibrinogen; Humans; Insulin Resistance; Life Style; Lipids; Male; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors; Triglycerides

Cognition and the risk of hospitalization for serious falls in the elderly: results from the Cardiovascular Health Study. - Welmerink, Diana B; Longstreth, W T; Lyles, Mary F; Fitzpatrick, Annette L (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Many elderly adults fall every year, sometimes resulting in serious injury and hospitalization. Although impaired cognition is a risk factor for injurious falls, little is known about cognitive decline above the threshold of impairment and risk of serious falls in community-dwelling seniors. METHODS: In total, 702 of 5,356 older adults participating in the Cardiovascular Health Study experienced an injurious fall between 1990 and 2005, as indicated by hospitalization records. General cognition was measured annually with the Modified Mini-Mental State Examination and processing speed with the Digit Symbol Substitution Test. The Cox regression model was used to calculate hazard ratio and 95% confidence interval with and without time-dependent covariates and adjusted for known risk factors. RESULTS: Participants with slightly decreased Digit Symbol Substitution Test scores were at increased risk for a serious fall (hazard ratio = 1.58, 95% confidence interval = 1.15-2.17). The risk continued to increase with each quartile decrease in Digit Symbol Substitution Test score. Participants without prevalent cardiovascular disease at baseline and decreased Modified Mini-Mental State Examination scores (80-89) had a 45% increased risk for a serious fall and those at high risk for dementia (<80) were at twice the risk as participants scoring above 90 (hazard ratio = 2.16, 95% confidence interval = 1.60-2.91). CONCLUSIONS: Both decreased general cognition and decreased processing speed appear to be potential risk factors for serious falls in the elderly. When assessing the risk of serious falls in elderly patients, clinicians should consider usual factors like gait instability and sensory impairment as well as less obvious ones such as cardiovascular disease and cognitive function in nondemented adults.
Keywords: Accidental Falls; Aged; Aged, 80 and over; Chi-Square Distribution; Cognition Disorders; Female; Follow-Up Studies; Geriatric Assessment; Hospitalization; Humans; Male; Mental Status Schedule; Physical Examination; Proportional Hazards Models; Risk Assessment; Risk Factors; Surveys and Questionnaires

Combined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study. - Wong, Nathan D; Lopez, Victor A; Roberts, Craig S; Solomon, Henry A; Burke, Gregory L; Kuller, Lewis; Tracy, Russell; Yanez, David; Psaty, Bruce M (Am J Hypertens, 2010)
BACKGROUND: Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events. METHODS: We studied 4,311 participants aged 65-98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD-including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years. RESULTS: CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80 mm Hg and LDL-C <100 mg/dl to 94.8 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl, and from 28.9 when BP <120/80 mm Hg and HDL >60 mg/dl to 87.1 for a BP >or=160/100 and HDL-C <40 mg/dl. Compared with those with BP <120/80 mm Hg with either LDL-C <100 mg/dl or HDL-C >60 mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl and 2.1 when BP >or=160/100 and HDL-C <40 mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90 mm Hg, but lower HDL-C also predicted CVD in those with higher BP. CONCLUSION: Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90 mm Hg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.
Keywords: Age Factors; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Female; Health Surveys; Humans; Likelihood Functions; Lipids; Male; Proportional Hazards Models; Sex Factors; Smoking; Socioeconomic Factors; United States

Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk. - Barnes, Deborah E; Covinsky, Kenneth E; Whitmer, Rachel A; Kuller, Lewis H; Lopez, Oscar L; Yaffe, Kristine (Alzheimers Dement, 2010)
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Diagnosis, Differential; Disability Evaluation; Early Diagnosis; Humans; National Health Programs; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; United States

Common genetic determinants of vitamin D insufficiency: a genome-wide association study. - Wang, Thomas J; Zhang, Feng; Richards, J Brent; Kestenbaum, Bryan; van Meurs, Joyce B; Berry, Diane; Kiel, Douglas P; Streeten, Elizabeth A; Ohlsson, Claes; Koller, Daniel L; Peltonen, Leena; Cooper, Jason D; et al. (Lancet, 2010)
BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
Keywords: Canada; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Cohort Studies; Dietary Supplements; Europe; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Homozygote; Humans; Immunoassay; International Cooperation; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Seasons; United States; Vitamin D; Vitamin D Deficiency

Common genetic variants associate with serum phosphorus concentration. - Kestenbaum, Bryan; Glazer, Nicole L; Köttgen, Anna; Felix, Janine F; Hwang, Shih-Jen; Liu, Yongmei; Lohman, Kurt; Kritchevsky, Stephen B; Hausman, Dorothy B; Petersen, Ann-Kristin; Gieger, Christian; Ried, Janina S; et al. (J Am Soc Nephrol, 2010)
Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
Keywords: Adult; Aged; European Continental Ancestry Group; Female; Fibroblast Growth Factors; Gene Frequency; Genetic Loci; Genetic Variation; Genome-Wide Association Study; Humans; Kidney; Male; Middle Aged; Phosphorus; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing; Sex Factors; Sodium-Phosphate Cotransporter Proteins, Type IIa

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. - Sotoodehnia, Nona; Isaacs, Aaron; de Bakker, Paul I W; Dörr, Marcus; Newton-Cheh, Christopher; Nolte, Ilja M; van der Harst, Pim; Müller, Martina; Eijgelsheim, Mark; Alonso, Alvaro; Hicks, Andrew A; Padmanabhan, Sandosh; et al. (Nat Genet, 2010)
The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
Keywords: Animals; Animals, Newborn; Chromosomes, Human; Computational Biology; Electrocardiography; Genetic Loci; Genome-Wide Association Study; Heart Conduction System; Humans; Mice; Mice, Transgenic; Models, Animal; Myocytes, Cardiac; NAV1.8 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Sodium Channels

Common variants in KCNN3 are associated with lone atrial fibrillation. - Ellinor, Patrick T; Lunetta, Kathryn L; Glazer, Nicole L; Pfeufer, Arne; Alonso, Alvaro; Chung, Mina K; Sinner, Moritz F; de Bakker, Paul I W; Mueller, Martina; Lubitz, Steven A; Fox, Ervin; Darbar, Dawood; et al. (Nat Genet, 2010)
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
Keywords: Adolescent; Adult; Aged; Atrial Fibrillation; Case-Control Studies; Cohort Studies; Female; Genome-Wide Association Study; Humans; Introns; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide; Small-Conductance Calcium-Activated Potassium Channels; Young Adult

Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. - O'Seaghdha, Conall M; Yang, Qiong; Glazer, Nicole L; Leak, Tennille S; Dehghan, Abbas; Smith, Albert V; Kao, W H Linda; Lohman, Kurt; Hwang, Shih-Jen; Johnson, Andrew D; Hofman, Albert; Uitterlinden, André G; et al. (Hum Mol Genet, 2010)
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
Keywords: Adult; Calcium; Female; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing

Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the Cardiovascular Health Study All Stars study. - Sanders, J L; Cappola, A R; Arnold, A M; Boudreau, R M; Chaves, P H; Robbins, J; Cushman, M; Newman, A B (J Gerontol A Biol Sci Med Sci, 2010)
INTRODUCTION: The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging. METHODS: DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996-1997 and 2005-2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005-2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline. RESULTS: After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline. CONCLUSIONS: In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
Keywords: Aged, 80 and over; Biomarkers; Cognition; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Gait; Geriatric Assessment; Hand Strength; Health Surveys; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Sex Factors; United States

C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. - Kaptoge, Stephen; Di Angelantonio, Emanuele; Lowe, Gordon; Pepys, Mark B; Thompson, Simon G; Collins, Rory; Danesh, John (Lancet, 2010)
BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality. INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.
Keywords: Alcohol Drinking; Biomarkers; Blood Pressure; Body Mass Index; C-Reactive Protein; Cholesterol; Coronary Disease; Databases, Factual; Diabetes Mellitus; Female; Fibrinogen; Humans; Interleukin-6; Leukocyte Count; Lung Diseases; Male; Middle Aged; Motor Activity; Neoplasms; Regression Analysis; Risk Assessment; Risk Factors; Serum Albumin; Sex Factors; Smoking; Stroke; Triglycerides

CRP gene variation and risk of community-acquired pneumonia. - Mukamal, Kenneth J; Pai, Jennifer K; O'Meara, Ellen S; Tracy, Russell P; Psaty, Bruce M; Kuller, Lewis H; Newman, Anne B; Yende, Sachin; Curhan, Gary C; Siscovick, David S; Rimm, Eric B (Respirology, 2010)
BACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain. METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires. RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels. CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.
Keywords: African Americans; Aged; Aged, 80 and over; Body Mass Index; C-Reactive Protein; Cohort Studies; Community-Acquired Infections; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Pneumonia; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Smoking

Cystatin C and sudden cardiac death risk in the elderly. - Deo, Rajat; Sotoodehnia, Nona; Katz, Ronit; Sarnak, Mark J; Fried, Linda F; Chonchol, Michel; Kestenbaum, Bryan; Psaty, Bruce M; Siscovick, David S; Shlipak, Michael G (Circ Cardiovasc Qual Outcomes, 2010)
BACKGROUND: Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease. METHODS AND RESULTS: The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. Sudden cardiac death (SCD) was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based estimated glomerular filtration rate (eGFR) tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10 000 person years in tertile 1, 25 events per 10 000 person years in tertile 2, and 32 events per 10 000 person-years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: hazards ratio=2.72; 95% confidence interval, 1.44 to 5.16 in tertile 2 and hazards ratio=2.67; 95% confidence interval, 1.33 to 5.35 in tertile 3. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10 000 person-years in tertile 1, 22 events per 10 000 person-years in tertile 2, and 27 events per 10 000 person-years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment. CONCLUSIONS: Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.
Keywords: Age Factors; Aged; Biomarkers; Chi-Square Distribution; Creatinine; Cystatin C; Death, Sudden, Cardiac; Female; Glomerular Filtration Rate; Humans; Incidence; Kidney Diseases; Longitudinal Studies; Male; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; United States; Up-Regulation

Diabetes and coronary heart disease as risk factors for mortality in older adults. - Carnethon, Mercedes R; Biggs, Mary L; Barzilay, Joshua; Kuller, Lewis H; Mozaffarian, Dariush; Mukamal, Kenneth; Smith, Nicholas L; Siscovick, David (Am J Med, 2010)
BACKGROUND: Type 2 diabetes has been described as a coronary heart disease (CHD) "risk equivalent." We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common. METHODS: The Cardiovascular Health Study is a longitudinal study of men and women (n=5784) aged > or =65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose > or =7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization. RESULTS: Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent=8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone. CONCLUSIONS: Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.
Keywords: Aged; Coronary Disease; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Prevalence; Risk Factors; Sex Distribution; Survival Rate; Time Factors; United States

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. - Sarwar, N; Gao, P; Seshasai, S R Kondapally; Gobin, R; Kaptoge, S; Di Angelantonio, E; Ingelsson, E; Lawlor, D A; Selvin, E; Stampfer, M; Stehouwer, C D A; Lewington, S; et al. (Lancet, 2010)
BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.
Keywords: Adult; Aged; Blood Glucose; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Fasting; Female; Humans; Male; Middle Aged; Risk Factors; Stroke

Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. - Gkrania-Klotsas, Effrossyni; Ye, Zheng; Cooper, Andrew J; Sharp, Stephen J; Luben, Robert; Biggs, Mary L; Chen, Liang-Kung; Gokulakrishnan, Kuppan; Hanefeld, Markolf; Ingelsson, Erik; Lai, Wen-An; Lin, Shih-Yi; et al. (PLoS One, 2010)
OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
Keywords: Adult; Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leukocyte Count; Male; Middle Aged; Prospective Studies

Dynamic cardiovascular risk assessment in elderly people. The role of repeated N-terminal pro-B-type natriuretic peptide testing. - deFilippi, Christopher R; Christenson, Robert H; Gottdiener, John S; Kop, Willem J; Seliger, Stephen L (J Am Coll Cardiol, 2010)
OBJECTIVES: This study sought to determine whether serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in community-dwelling elderly people would provide additional prognostic information to that from traditional risk factors. BACKGROUND: Accurate cardiovascular risk stratification is challenging in elderly people. METHODS: NT-proBNP was measured at baseline and 2 to 3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal CHS (Cardiovascular Health Study). This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders. RESULTS: NT-proBNP levels in the highest quintile (>267.7 pg/ml) were independently associated with greater risks of HF (hazard ratio [HR]: 3.05; 95% confidence interval [CI]: 2.46 to 3.78) and cardiovascular death (HR: 3.02; 95% CI: 2.36 to 3.86) compared with the lowest quintile (<47.5 pg/ml). The inflection point for elevated risk occurred at NT-proBNP 190 pg/ml. Among participants with initially low NT-proBNP (<190 pg/ml), those who developed a >25% increase on follow-up to >190 pg/ml (21%) were at greater adjusted risk of HF (HR: 2.13; 95% CI: 1.68 to 2.71) and cardiovascular death (HR: 1.91; 95% CI: 1.43 to 2.53) compared with those with sustained low levels. Among participants with initially high NT-proBNP, those who developed a >25% increase (40%) were at higher risk of HF (HR: 2.06; 95% CI: 1.56 to 2.72) and cardiovascular death (HR: 1.88; 95% CI: 1.37 to 2.57), whereas those who developed a >25% decrease to <or=190 pg/ml (15%) were at lower risk of HF (HR: 0.58; 95% CI: 0.36 to 0.93) and cardiovascular death (HR: 0.57; 95% CI: 0.32 to 1.01) compared with those with unchanged high values. CONCLUSIONS: NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time, and these fluctuations reflect dynamic changes in cardiovascular risk.
Keywords: Aged; Biomarkers; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; United States

Egg consumption and risk of type 2 diabetes in older adults. - Djoussé, Luc; Kamineni, Aruna; Nelson, Tracy L; Carnethon, Mercedes; Mozaffarian, Dariush; Siscovick, David; Mukamal, Kenneth J (Am J Clin Nutr, 2010)
BACKGROUND: Type 2 diabetes (T2D) remains an important public health issue in the United States. There are limited and inconsistent data on the association between egg consumption and fasting glucose or incident diabetes. OBJECTIVES: We assessed the association between egg intake and incident diabetes in older adults. DESIGN: In this prospective study of 3898 men and women from the Cardiovascular Health Study (1989-2007), we assessed egg consumption by using a picture-sorted food questionnaire and ascertained incident T2D annually by using information on hypoglycemic agents and plasma glucose. We used Cox proportional hazards models to estimate adjusted relative risks. RESULTS: During a mean follow-up of 11.3 y, 313 new cases of T2D occurred. Crude incidence rates of T2D were 7.39, 6.83, 7.00, 6.72, and 12.20 per 1000 person-years in people who reported egg consumption of never, <1 egg/mo, 1-3 eggs/mo, 1-4 eggs/wk, and almost daily, respectively. In multivariable-adjusted models, there was no association between egg consumption and increased risk of T2D in either sex and overall. In a secondary analysis, dietary cholesterol was not associated with incident diabetes (P for trend = 0.47). In addition, egg consumption was not associated with clinically meaningful differences in fasting glucose, fasting insulin, or measures of insulin resistance despite small absolute analytic differences that were significant. CONCLUSION: In this cohort of older adults with limited egg intake, there was no association between egg consumption or dietary cholesterol and increased risk of incident T2D.
Keywords: Aged; Blood Glucose; Cholesterol, Dietary; Diabetes Mellitus, Type 2; Diet; Diet Surveys; Eggs; Feeding Behavior; Female; Humans; Insulin; Insulin Resistance; Male; Proportional Hazards Models; Prospective Studies; Risk Factors; Surveys and Questionnaires

European ancestry as a risk factor for atrial fibrillation in African Americans. - Marcus, Gregory M; Alonso, Alvaro; Peralta, Carmen A; Lettre, Guillaume; Vittinghoff, Eric; Lubitz, Steven A; Fox, Ervin R; Levitzky, Yamini S; Mehra, Reena; Kerr, Kathleen F; Deo, Rajat; Sotoodehnia, Nona; et al. (Circulation, 2010)
BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF. METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results. CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
Keywords: African Americans; Aged; Atrial Fibrillation; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Risk Factors

Fish consumption, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. - Virtanen, Jyrki K; Mozaffarian, Dariush; Cauley, Jane A; Mukamal, Kenneth J; Robbins, John; Siscovick, David S (J Bone Miner Res, 2010)
Marine n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be beneficial for bone health, but few studies have investigated the association with fish consumption. Our aim was to study associations of fish and EPA + DHA consumption with bone mineral density (BMD) and hip fracture risk and determine whether high linoleic acid (LA) intake, the major dietary n-6 PUFA, modifies the associations. The study population consisted of 5045 participants aged 65 years and older from the Cardiovascular Health Study. Data on BMD were available for 1305 participants. Food-frequency questionnaire was used to assess dietary intake, and hip fracture incidence was assessed prospectively by review of hospitalization records. After multivariable adjustment, femoral neck BMD was 0.01 g/cm(2) lower in the highest versus lowest tuna/other-fish intake category (p = .05 for trend). EPA + DHA intake (higher versus lower median of 0.32 g/day) was associated with lower femoral neck BMD (0.66 versus 0.71 g/cm(2), p < .001) among those with LA intake greater than the median 12.1 g/day (p = .03 for interaction). No significant associations were found with total-hip BMD. During mean follow-up of 11.1 years, 505 hip fractures occurred. Fish or EPA + DHA consumption was not significantly associated with fracture incidence [hazard ratio (HR) for extreme categories: HR = 1.23, 95% confidence interval (CI) 0.83-1.84 for tuna/other fish; HR = 1.16, 95% CI 0.91-1.49 for fried fish; and HR = 0.98, 95% CI 0.71-1.36 for EPA + DHA]. High LA intake did not modify these associations. In this large prospective cohort of older adults, fish consumption was associated with very small differences in BMD and had no association with hip fracture risk.
Keywords: Aged; Aged, 80 and over; Animals; Bone Density; Diet; Female; Fishes; Hip Fractures; Humans; Male; Risk Factors; Surveys and Questionnaires

Food sources of individual plasma phospholipid trans fatty acid isomers: the Cardiovascular Health Study. - Micha, Renata; King, Irena B; Lemaitre, Rozenn N; Rimm, Eric B; Sacks, Frank; Song, Xiaoling; Siscovick, David S; Mozaffarian, Dariush (Am J Clin Nutr, 2010)
BACKGROUND: The overall consumption of trans fatty acids (TFAs) increases the risk of coronary artery disease. However, multiple TFA isomers exist, each with potentially different health effects. Different food sources of these specific TFA isomers are not well established. OBJECTIVE: Our objective was to determine the major independent food sources of specific TFA isomers. DESIGN: We investigated relations of major potential food sources of TFAs, as assessed by serial food-frequency questionnaires, with 10 plasma phospholipid TFA isomers [5 trans (t-) 18:1, 3 t-18:2, and 2 t-16:1] in 3330 older adults in the Cardiovascular Health Study, a community-based multicenter cohort. Stepwise regression was used to identify independent major food sources of individual plasma phospholipid TFA isomers, which were adjusted for demographic, lifestyle, and dietary factors. RESULTS: All 5 t-18:1 isomers were similarly associated with foods commonly made with partially hydrogenated vegetable oils (PHVOs), including biscuits (0.51 higher SD of total 18:1 fatty acid concentrations per serving/d, P < 0.01), chips and/or popcorn (0.33 higher SD per serving/d, P = 0.02), margarine (0.32 higher SD per serving/d, P < 0.001), fried foods (0.32 higher SD per serving/d, P = 0.04), and bakery foods (0.23 higher SD per serving/d, P = 0.02). Each of the t-18:2 isomers were associated only with bakery foods (0.50 higher SD of total 18:2 fatty acid concentrations per serving/d, P < 0.001). Ruminant foods were major correlates of t-16:1n-7, including red meats (0.72 higher SD per serving/d, P < 0.001), butter (0.43 higher SD per serving/d, P < 0.001), and higher-fat dairy (0.37 higher SD per serving/d, P < 0.001). In contrast, t-16:1n-9 were derived mainly from margarine (0.31 higher SD per serving/d, P < 0.001). CONCLUSIONS: t-18:1 Isomers are similarly derived from multiple PHVO-containing foods. In contrast, t-18:2 and t-16:1n-9 isomers are derived from more-specific types of PHVO-containing foods. Ruminant foods are major sources of t-16:1n-7. Different TFA isomers and dietary sources should be considered when investigating health effects and interventions to lower TFAs.
Keywords: Aged; Cardiovascular System; Diet; Diet Surveys; Dietary Fats; Female; Food Analysis; Health; Humans; Hydrogenation; Isomerism; Male; Phospholipids; Plant Oils; Regression Analysis; Surveys and Questionnaires; Trans Fatty Acids

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. - Ikram, M Kamran; Sim, Xueling; Xueling, Sim; Jensen, Richard A; Cotch, Mary Frances; Hewitt, Alex W; Ikram, M Arfan; Wang, Jie Jin; Klein, Ronald; Klein, Barbara E K; Breteler, Monique M B; Cheung, Ning; et al. (PLoS Genet, 2010)
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Child; Child, Preschool; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 6; Cohort Studies; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Microcirculation; Middle Aged; Polymorphism, Single Nucleotide; Retinal Vessels; Young Adult

Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. - McGovern, Dermot P B; Jones, Michelle R; Taylor, Kent D; Marciante, Kristin; Yan, Xiaofei; Dubinsky, Marla; Ippoliti, Andy; Vasiliauskas, Eric; Berel, Dror; Derkowski, Carrie; Dutridge, Deb; Fleshner, Phil; et al. (Hum Mol Genet, 2010)
Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
Keywords: Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; Crohn Disease; Female; Fucosyltransferases; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Young Adult

Genetic ancestry in lung-function predictions. - Kumar, Rajesh; Seibold, Max A; Aldrich, Melinda C; Williams, L Keoki; Reiner, Alex P; Colangelo, Laura; Galanter, Joshua; Gignoux, Christopher; Hu, Donglei; Sen, Saunak; Choudhry, Shweta; Peterson, Edward L; et al. (N Engl J Med, 2010)
BACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American. METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations. RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants. CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
Keywords: Adolescent; Adult; African Americans; Aged; Aged, 80 and over; Female; Forced Expiratory Volume; Genetic Markers; Genotype; Humans; Linear Models; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Reference Values; Respiratory Function Tests; Vital Capacity; Young Adult

Genetic predictors of medically refractory ulcerative colitis. - Haritunians, Talin; Taylor, Kent D; Targan, Stephan R; Dubinsky, Marla; Ippoliti, Andrew; Kwon, Soonil; Guo, Xiuqing; Melmed, Gil Y; Berel, Dror; Mengesha, Emebet; Psaty, Bruce M; Glazer, Nicole L; et al. (Inflamm Bowel Dis, 2010)
BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC. METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls. RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)). CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
Keywords: Acute Disease; Adolescent; Adult; Cohort Studies; Colectomy; Colitis, Ulcerative; Female; Genetic Loci; Genome-Wide Association Study; Humans; Major Histocompatibility Complex; Male; Polymorphism, Single Nucleotide; Risk Factors; Severity of Illness Index; Tumor Necrosis Factor Ligand Superfamily Member 15; Young Adult

Genome-wide analysis of genetic loci associated with Alzheimer disease. - Seshadri, Sudha; Fitzpatrick, Annette L; Ikram, M Arfan; DeStefano, Anita L; Gudnason, Vilmundur; Boada, Merce; Bis, Joshua C; Smith, Albert V; Carassquillo, Minerva M; Lambert, Jean Charles; Harold, Denise; Schrijvers, Elisabeth M C; et al. (JAMA, 2010)
CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE: Presence of Alzheimer disease. RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
Keywords: Age of Onset; Aged; Alzheimer Disease; Case-Control Studies; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Odds Ratio; Polymorphism, Single Nucleotide

Genome-wide association analysis identifies multiple loci related to resting heart rate. - Eijgelsheim, Mark; Newton-Cheh, Christopher; Sotoodehnia, Nona; de Bakker, Paul I W; Müller, Martina; Morrison, Alanna C; Smith, Albert V; Isaacs, Aaron; Sanna, Serena; Dörr, Marcus; Navarro, Pau; Fuchsberger, Christian; et al. (Hum Mol Genet, 2010)
Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
Keywords: Adult; Aged; Base Pairing; Cohort Studies; Female; Genetic Loci; Genome, Human; Genome-Wide Association Study; Heart Rate; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Rest

Genome-wide association identifies multiple ulcerative colitis susceptibility loci. - McGovern, Dermot P B; Gardet, Agnès; Törkvist, Leif; Goyette, Philippe; Essers, Jonah; Taylor, Kent D; Neale, Benjamin M; Ong, Rick T H; Lagacé, Caroline; Li, Chun; Green, Todd; Stevens, Christine R; et al. (Nat Genet, 2010)
Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
Keywords: Colitis, Ulcerative; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Membrane Proteins; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Receptors, IgG

Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. - Levy, Daniel; Neuhausen, Susan L; Hunt, Steven C; Kimura, Masayuki; Hwang, Shih-Jen; Chen, Wei; Bis, Joshua C; Fitzpatrick, Annette L; Smith, Erin; Johnson, Andrew D; Gardner, Jeffrey P; Srinivasan, Sathanur R; et al. (Proc Natl Acad Sci U S A, 2010)
Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
Keywords: Cohort Studies; Genome-Wide Association Study; Genotype; Humans; Leukocytes; Polymorphism, Single Nucleotide; Receptors, CXCR4; Telomere; Telomere-Binding Proteins

Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. - Debette, Stephanie; Bis, Joshua C; Fornage, Myriam; Schmidt, Helena; Ikram, M Arfan; Sigurdsson, Sigurdur; Heiss, Gerardo; Struchalin, Maksim; Smith, Albert V; van der Lugt, Aad; DeCarli, Charles; Lumley, Thomas; et al. (Stroke, 2010)
BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct). RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
Keywords: African Americans; Aged; Brain; Brain Infarction; Cohort Studies; DNA Mutational Analysis; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Magnetic Resonance Imaging; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies

Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. - Meyer, Tamra E; Verwoert, Germaine C; Hwang, Shih-Jen; Glazer, Nicole L; Smith, Albert V; van Rooij, Frank J A; Ehret, Georg B; Boerwinkle, Eric; Felix, Janine F; Leak, Tennille S; Harris, Tamara B; Yang, Qiong; et al. (PLoS Genet, 2010)
Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
Keywords: Adult; Aged; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Magnesium; Male; Middle Aged; Polymorphism, Single Nucleotide; Potassium; Sodium

Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. - Arking, Dan E; Reinier, Kyndaron; Post, Wendy; Jui, Jonathan; Hilton, Gina; O'Connor, Ashley; Prineas, Ronald J; Boerwinkle, Eric; Psaty, Bruce M; Tomaselli, Gordon F; Rea, Thomas; Sotoodehnia, Nona; et al. (PLoS One, 2010)
BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01). CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
Keywords: Aged; Alleles; Case-Control Studies; Cohort Studies; Death, Sudden, Cardiac; Ethnic Groups; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Glypicans; Heart Diseases; Humans; Male; Middle Aged; Models, Genetic; Oligonucleotide Array Sequence Analysis; Oregon; Polymorphism, Single Nucleotide

Genome-wide association study of PR interval. - Pfeufer, Arne; van Noord, Charlotte; Marciante, Kristin D; Arking, Dan E; Larson, Martin G; Smith, Albert Vernon; Tarasov, Kirill V; Müller, Martina; Sotoodehnia, Nona; Sinner, Moritz F; Verwoert, Germaine C; Li, Man; et al. (Nat Genet, 2010)
The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
Keywords: Aged; Atrial Fibrillation; Cohort Studies; Electrocardiography; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Heart Conduction System; Humans; Male; Meta-Analysis as Topic

Genome-wide meta-analyses identify multiple loci associated with smoking behavior. (Nat Genet, 2010)
Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
Keywords: Age Factors; Alleles; Chromosome Mapping; Female; Genome; Genome-Wide Association Study; Genotype; Humans; Male; Molecular Epidemiology; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Receptors, Nicotinic; Smoking

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. - Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C; Wang, Kai; Radford-Smith, Graham L; Ahmad, Tariq; Lees, Charlie W; Balschun, Tobias; Lee, James; Roberts, Rebecca; Anderson, Carl A; Bis, Joshua C; et al. (Nat Genet, 2010)
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
Keywords: Computational Biology; Crohn Disease; Genetic Linkage; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Reproducibility of Results

Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. - Morrison, Alanna C; Felix, Janine F; Cupples, L Adrienne; Glazer, Nicole L; Loehr, Laura R; Dehghan, Abbas; Demissie, Serkalem; Bis, Joshua C; Rosamond, Wayne D; Aulchenko, Yurii S; Wang, Ying A; Haritunians, Talin; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance. CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
Keywords: African Americans; Aged; Aged, 80 and over; Chemokines; Cohort Studies; European Continental Ancestry Group; Female; Genome-Wide Association Study; Genotype; Heart Failure; Humans; Introns; Male; MARVEL Domain-Containing Proteins; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Geriatric impairments and disability: the cardiovascular health study. - Chaudhry, Sarwat I; McAvay, Gail; Ning, Yuming; Allore, Heather G; Newman, Anne B; Gill, Thomas M (J Am Geriatr Soc, 2010)
OBJECTIVES: To determine the relative importance of geriatric impairments (in muscle strength, physical capacity, cognition, vision, hearing, and psychological status) and chronic diseases in predicting subsequent functional disability in longitudinal analyses. DESIGN: Longitudinal data from the Cardiovascular Health Study were analyzed. Multivariable Cox hazards regression modeling was used to analyze associations between time-dependent predictors and onset of disability in activities of daily living (ADLs) and mobility. SETTING: Four communities across the United States (Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Allegheny County, PA). PARTICIPANTS: Five thousand eight hundred eighty-eight elderly persons. MEASUREMENTS: Data were collected annually through in-person examinations. RESULTS: ADL disability developed in 15% of participants and mobility disability in 30%. A single multivariable model was developed that included demographics, marital status, body mass index, and number of impairments and diseases. The hazard ratios (HRs) of having one, two, and three or more geriatric impairments (vs none) for the outcome of ADL disability were 2.12 (95% confidence interval (CI)=1.63-2.75), 4.25 (95% CI=3.30-5.48), and 7.87 (95% CI=6.10-10.17), respectively, and for having one, two, and three or more chronic diseases were 1.75 (95% CI=1.41-2.19), 2.45 (95% CI=1.95-3.07), and 3.26 (95% CI=2.53-4.19), respectively. Similarly, the HRs of having one, two, and three or more impairments for the outcome of mobility disability were 1.48 (95% CI=1.27-1.73), 2.08 (95% CI=1.77-2.45), and 3.70 (95% CI=3.09-4.42), respectively, and for having one, two, and three or more diseases were 2.06 (95% CI=1.76-2.40), 2.80 (95% CI=2.36-3.31), and 4.20 (95% CI=3.44-5.14), respectively. CONCLUSION: Number of geriatric impairments was more strongly associated than number of chronic diseases with subsequent ADL disability and nearly as strongly associated with the subsequent mobility disability.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Cardiac Rehabilitation; Cardiovascular Diseases; Disabled Persons; Female; Follow-Up Studies; Geriatric Assessment; Health Status; Humans; Male; Morbidity; Retrospective Studies; Risk Factors; Time Factors; United States

Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly. - Chonchol, M; Katz, R; Fried, L F; Sarnak, M J; Siscovick, D S; Newman, A B; Strotmeyer, E S; Bertoni, A; Shlipak, M G (Nutr Metab Cardiovasc Dis, 2010)
BACKGROUND AND AIMS: Glycosylated hemoglobin (HbA(1c)) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA(1c) may be associated with an increased risk of death and cardiovascular mortality in older adults. METHODS AND RESULTS: We evaluated the association between HbA(1c) with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals > or =65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA(1c) and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA(1c) groups were: 4.4% per year, 4.3% per year and 4.6% per year for tertile 1 (< or =5.6%), tertile 2 (5.61-6.20%) and tertile 3 (> or =6.21%), respectively. In unadjusted and fully adjusted analyses, baseline HbA(1c) was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95% confidence interval 0.91-1.47] and hazard ratio: 1.31 [95% confidence interval 0.90-1.93], respectively for the highest HbA(1c) tertile compared with the lowest). CONCLUSION: These results suggest that HbA(1c) does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.
Keywords: Aged; Aged, 80 and over; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Disease Progression; Female; Glycated Hemoglobin A; Health Surveys; Heart Failure; Humans; Incidence; Male; Myocardial Infarction; Risk Factors; Statistics as Topic; Stroke; United States

Health benefits of increased walking for sedentary, generally healthy older adults: using longitudinal data to approximate an intervention trial. - Diehr, Paula; Hirsch, Calvin (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Older adults are often advised to walk more, but randomized trials have not conclusively established the benefits of walking in this age group. Typical analyses based on observational data may have biased results. Here, we propose a "limited-bias," more interpretable estimate of the health benefits to sedentary healthy older adults of walking more, using longitudinal data from the Cardiovascular Health Study. METHODS: The number of city blocks walked per week, collected annually, was classified as sedentary (<7 blocks per week), somewhat active, or active (>or=28). Analysis was restricted to persons sedentary and healthy in the first 2 years. In Year 3, some became more active (the treatment groups). Self-rated health at Year 5 (follow-up) was regressed on walking at Year 3, with additional covariates from Year 2, when all were sedentary. RESULTS: At follow-up, 83.5% of those active at baseline had excellent, very good, or good self-rated health, as compared with 63.9% of the sedentary, an apparent benefit of 19.6 percentage points. After covariate adjustment, the limited-bias estimate of the benefit was 11.2 percentage points (95% confidence interval 3.7-18.6). Ten different outcome measures showed a benefit, ranging from 5 to 11 percentage points. Estimates from other study designs were smaller, less interpretable, and potentially more biased. CONCLUSIONS: In longitudinal studies where walking and health are ascertained at every wave, limited-bias estimates can provide better estimates of the benefits of walking. A surprisingly small increase in walking was associated with meaningful health benefits.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Data Interpretation, Statistical; Female; Health Status; Health Surveys; Humans; Longitudinal Studies; Male; Regression Analysis; Sedentary Lifestyle; Walking

Hip fractures and heart failure: findings from the Cardiovascular Health Study. - Carbone, Laura; Bůzková, Petra; Fink, Howard A; Lee, Jennifer S; Chen, Zhao; Ahmed, Ali; Parashar, Susmita; Robbins, John R (Eur Heart J, 2010)
AIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis. METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone. CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.
Keywords: Aged; Female; Heart Failure; Hip Fractures; Humans; Incidence; Male; Risk Factors; United States

Hundreds of variants clustered in genomic loci and biological pathways affect human height. - Lango Allen, Hana; Estrada, Karol; Lettre, Guillaume; Berndt, Sonja I; Weedon, Michael N; Rivadeneira, Fernando; Willer, Cristen J; Jackson, Anne U; Vedantam, Sailaja; Raychaudhuri, Soumya; Ferreira, Teresa; Wood, Andrew R; et al. (Nature, 2010)
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Keywords: Body Height; Chromosomes, Human, Pair 3; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Metabolic Networks and Pathways; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide

Impaired kidney function and atrial fibrillation in elderly subjects. - Deo, Rajat; Katz, Ronit; Kestenbaum, Bryan; Fried, Linda; Sarnak, Mark J; Psaty, Bruce M; Siscovick, David S; Shlipak, Michael G (J Card Fail, 2010)
BACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons. METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7%) had AF at baseline and 579 (13%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95% CI [0.80-1.76] in quartile 2; HR=2.00, 95% CI [1.38-2.88] in quartile 3; and HR=2.87, 95% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95% CI [1.07-1.75] in quartile 2; HR=1.43, 95% CI [1.11-1.84] in quartile 3; and HR=1.88, 95% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses. CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.
Keywords: Age Factors; Aged; Aged, 80 and over; Atrial Fibrillation; Cohort Studies; Cross-Sectional Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Male

Independent susceptibility markers for atrial fibrillation on chromosome 4q25. - Lubitz, Steven A; Sinner, Moritz F; Lunetta, Kathryn L; Makino, Seiko; Pfeufer, Arne; Rahman, Rosanna; Veltman, Caroline E; Barnard, John; Bis, Joshua C; Danik, Stephan P; Sonni, Akshata; Shea, Marisa A; et al. (Circulation, 2010)
BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
Keywords: Aged; Aged, 80 and over; Atrial Fibrillation; Chromosome Mapping; Chromosomes, Human, Pair 4; European Continental Ancestry Group; Female; Genetic Markers; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study. - Keller, Christopher; Katz, Ronit; Sarnak, Mark J; Fried, Linda F; Kestenbaum, Bryan; Cushman, Mary; Shlipak, Michael G (Nephrol Dial Transplant, 2010)
BACKGROUND: Cross-sectional studies have demonstrated a consistent and linear association between circulating inflammatory markers and kidney function. The objective of this study was to determine whether elevated markers of inflammation are independently associated with longitudinal kidney function decline. METHODS: This study included 4128 subjects from the Cardiovascular Health Study. Cystatin C was measured at baseline, 3 years later and 7 years later; eligible subjects had at least two measures. Cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) was estimated, and rapid kidney function decline was defined as an annual loss of eGFR(cysC) >3 mL/min/1.73 m(2). Predictors included ten inflammatory and procoagulant biomarkers: C-reactive protein, interleukin-6, intercellular adhesion molecule-1, white blood cell count, fibrinogen, factor VII, factor VIII, D-dimer, plasmin-antiplasmin complex and serum albumin. RESULTS: During the study, 1059 subjects (26%) had a rapid decline in kidney function. In contrast to the other nine inflammatory or procoagulant biomarkers, serum albumin had a consistent and inverse association with rapid kidney function decline [final adjusted logistic regression model: 1.14-fold increased odds (95% CI 1.06-1.23) of rapid decline per standard deviation lower albumin]. The lowest quartile of albumin had an odds ratio of 1.55 (95% CI 1.23-1.96) for rapid decline compared with the highest quartile. These associations persisted after adjusting the albumin models for CRP, IL-6 and fibrinogen. CONCLUSIONS: In contrast to nine other inflammatory and procoagulant markers, only lower baseline levels of serum albumin were consistently associated with a rapid decline in kidney function, as measured by cystatin C-based eGFR.
Keywords: Aged; Biomarkers; C-Reactive Protein; Cohort Studies; Cystatin C; Female; Glomerular Filtration Rate; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Kidney; Logistic Models; Longitudinal Studies; Male; Prospective Studies; Serum Albumin

Interaction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study. - Carty, Cara L; Heagerty, Patrick; Heckbert, Susan R; Jarvik, Gail P; Lange, Leslie A; Cushman, Mary; Tracy, Russell P; Reiner, Alexander P (Ann Hum Genet, 2010)
The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.
Keywords: Aged; Cardiovascular Diseases; Carotid Arteries; Female; Fibrinogen; Genetic Predisposition to Disease; Genetic Variation; Humans; Interleukin-6; Male; Models, Biological; Myocardial Infarction; Polymorphism, Single Nucleotide; Risk; Stroke

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. - Nettleton, Jennifer A; McKeown, Nicola M; Kanoni, Stavroula; Lemaitre, Rozenn N; Hivert, Marie-France; Ngwa, Julius; van Rooij, Frank J A; Sonestedt, Emily; Wojczynski, Mary K; Ye, Zheng; Tanaka, Tosh; Garcia, Melissa; et al. (Diabetes Care, 2010)
OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
Keywords: Adult; Aged; Blood Glucose; Edible Grain; European Continental Ancestry Group; Fasting; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide

Intravenous tissue plasminogen activator and stroke in the elderly. - Longstreth, W T; Katz, Ronit; Tirschwell, David L; Cushman, Mary; Psaty, Bruce M (Am J Emerg Med, 2010)
OBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain. METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995. RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1%; 95% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes. CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.
Keywords: Aged, 80 and over; Female; Fibrinolytic Agents; Humans; Longitudinal Studies; Male; Placebos; Randomized Controlled Trials as Topic; Stroke; Tissue Plasminogen Activator; Treatment Outcome; United States

Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. - Barbalic, Maja; Dupuis, Josée; Dehghan, Abbas; Bis, Joshua C; Hoogeveen, Ron C; Schnabel, Renate B; Nambi, Vijay; Bretler, Monique; Smith, Nicholas L; Peters, Annette; Lu, Chen; Tracy, Russell P; et al. (Hum Mol Genet, 2010)
P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.
Keywords: ABO Blood-Group System; Blood Platelets; Enzyme-Linked Immunosorbent Assay; European Continental Ancestry Group; Fluorescence; Genome-Wide Association Study; Humans; Intercellular Adhesion Molecule-1; P-Selectin

Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. - Thompson, Alexander; Gao, Pei; Orfei, Lia; Watson, Sarah; Di Angelantonio, Emanuele; Kaptoge, Stephen; Ballantyne, Christie; Cannon, Christopher P; Criqui, Michael; Cushman, Mary; Hofman, Albert; Packard, Chris; et al. (Lancet, 2010)
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Blood Pressure; Coronary Disease; Female; Humans; Linear Models; Lipids; Male; Middle Aged; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Systole

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and risk of cardiovascular disease in older adults: results from the Cardiovascular Health Study. - Jenny, Nancy Swords; Solomon, Cam; Cushman, Mary; Tracy, Russell P; Nelson, Jeanenne J; Psaty, Bruce M; Furberg, Curt D (Atherosclerosis, 2010)
OBJECTIVE: To examine associations between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults. METHODS: We examined associations of Lp-PLA(2) mass and activity with incident myocardial infarction (MI; n=508), stroke (n=565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3949 older adults, aged > or =65 years at baseline, from the Cardiovascular Health Study (CHS). RESULTS: Lp-PLA(2) was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA(2) mass were 1.49 (1.19-1.85) for MI, 1.21 (0.98-1.49) for stroke and 1.11 (0.92-1.33) for CVD death. The highest tertile of Lp-PLA(2) activity was associated with MI (1.36; 1.09-1.70) and CVD death (1.23; 1.02-1.50). Combined Lp-PLA(2) tertile 3 and CRP>3mg/l, compared to Lp-PLA(2) tertile 1 and CRP<1mg/l, was associated with MI (2.29; 1.49-3.52) for Lp-PLA(2) mass and MI (1.66; 1.10-2.51) and CVD death (1.57; 1.08-2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone ( approximately 20% excess risk) and activity added excess risk for CVD death ( approximately 12%). CONCLUSION: Lp-PLA(2) mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA(2) and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA(2) to identify older individuals at risk for CVD.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; C-Reactive Protein; Cardiovascular Diseases; Female; Humans; Myocardial Infarction; Population Surveillance; Prospective Studies; Risk; Stroke

Long-term retention of older adults in the Cardiovascular Health Study: implications for studies of the oldest old. - Strotmeyer, Elsa S; Arnold, Alice M; Boudreau, Robert M; Ives, Diane G; Cushman, Mary; Robbins, John A; Harris, Tamara B; Newman, Anne B (J Am Geriatr Soc, 2010)
OBJECTIVES: To describe retention according to age and visit type (clinic, home, telephone) and to determine characteristics associated with visit types for a longitudinal epidemiological study in older adults. DESIGN: Longitudinal cohort study. SETTING: Four U.S. clinical sites. PARTICIPANTS: Five thousand eight hundred eighty-eight Cardiovascular Health Study (CHS) participants aged 65 to 100 at 1989/90 or 1992/93 enrollment (58.6% female; 15.7% black). CHS participants were contacted every 6 months, with annual assessments through 1999 and in 2005/06 for the All Stars Study visit of the CHS cohort (aged 77-102; 66.5% female; 16.6% black). MEASUREMENTS: All annual contacts through 1999 (n=43,772) and for the 2005/06 visit (n=1,942). RESULTS: CHS had 43,772 total participant contacts from 1989 to 1999: 34,582 clinic visits (79.0%), 2,238 refusals (5.1%), 4,401 telephone visits (10.1%), 1,811 home visits (4.1%), and 740 other types (1.7%). In 2005/06, the All Stars participants of the CHS cohort had 36.6% clinic, 22.3% home, and 41.1% telephone visits. Compared with participants aged 65 to 69, odds ratios of not attending a CHS clinic visit were 1.82 (95% confidence interval (CI)=1.54-2.13), 2.94 (95% CI=2.45-3.57), 4.55 (95% CI=3.70-5.56), and 9.09 (95% CI=7.69-11.11) for those aged 70 to 74, 75 to 79, 80 to 84, and 85 and older, respectively, in sex-adjusted regression. In multivariable regression, participants with a 2005/06 clinic visit were younger, more likely to be male and in good health, and had had better cognitive and physical function 7 years earlier than participants with other visit types. Participants with home, telephone, and missing visits were similar on characteristics measured 7 years earlier. CONCLUSION: Offering home, telephone, and proxy visits are essential to optimizing follow-up of aging cohorts. Home visits increased in-person retention from 36.5% to 58.8% and diversified the cohort with respect to age, health, and physical functioning.
Keywords: Age Factors; Aged; Aged, 80 and over; Ambulatory Care Facilities; Analysis of Variance; Cardiovascular Diseases; Chi-Square Distribution; Epidemiologic Studies; Female; Geriatric Assessment; House Calls; Humans; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Patient Dropouts; Patient Selection; Research Subjects; Telephone; United States

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. - Hancock, Dana B; Eijgelsheim, Mark; Wilk, Jemma B; Gharib, Sina A; Loehr, Laura R; Marciante, Kristin D; Franceschini, Nora; van Durme, Yannick M T A; Chen, Ting-Hsu; Barr, R Graham; Schabath, Matthew B; Couper, David J; et al. (Nat Genet, 2010)
Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
Keywords: Databases, Genetic; Female; Forced Expiratory Volume; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Lung; Lung Diseases; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Spirometry; Vital Capacity

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. - Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; et al. (Nat Genet, 2010)
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Keywords: Adipose Tissue; Age Factors; Chromosome Mapping; Female; Genome, Human; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Sex Characteristics; Waist-Hip Ratio

A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. - Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L; Garcia, Melissa E; Slagboom, P Eline; Christensen, Kaare; Arnold, Alice M; Aspelund, Thor; Aulchenko, Yurii S; Benjamin, Emelia J; Christiansen, Lene; D'Agostino, Ralph B; et al. (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Cohort Studies; Confidence Intervals; Female; Genome-Wide Association Study; Genotype; Humans; Longevity; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. - Yang, Qiong; Köttgen, Anna; Dehghan, Abbas; Smith, Albert V; Glazer, Nicole L; Chen, Ming-Huei; Chasman, Daniel I; Aspelund, Thor; Eiriksdottir, Gudny; Harris, Tamara B; Launer, Lenore; Nalls, Michael; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
Keywords: Cardiovascular Diseases; Coronary Disease; Female; Genetic Loci; Genome-Wide Association Study; Gout; Humans; Male; Risk Factors; Uric Acid

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. - Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Soranzo, Nicole; Jackson, Anne U; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Gloyn, Anna L; Lindgren, Cecilia M; Mägi, Reedik; et al. (Nat Genet, 2010)
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Keywords: Adolescent; Adult; Alleles; Blood Glucose; Child; Databases, Genetic; Diabetes Mellitus, Type 2; DNA Copy Number Variations; Fasting; Gene Expression Regulation; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeostasis; Humans; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Reproducibility of Results

New loci associated with kidney function and chronic kidney disease. - Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Glazer, Nicole L; Parsa, Afshin; Gao, Xiaoyi; Yang, Qiong; Smith, Albert V; O'Connell, Jeffrey R; Li, Man; et al. (Nat Genet, 2010)
Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
Keywords: Cohort Studies; Creatinine; Cystatin C; Diet; Europe; Genetic Markers; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Models, Genetic; Risk Factors

A novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study. - Caffo, Brian; Diener-West, Marie; Punjabi, Naresh M; Samet, Jonathan (Sleep, 2010)
This manuscript considers a data-mining approach for the prediction of mild obstructive sleep disordered breathing, defined as an elevated respiratory disturbance index (RDI), in 5,530 participants in a community-based study, the Sleep Heart Health Study. The prediction algorithm was built using modern ensemble learning algorithms, boosting in specific, which allowed for assessing potential high-dimensional interactions between predictor variables or classifiers. To evaluate the performance of the algorithm, the data were split into training and validation sets for varying thresholds for predicting the probability of a high RDI (≥7 events per hour in the given results). Based on a moderate classification threshold from the boosting algorithm, the estimated post-test odds of a high RDI were 2.20 times higher than the pre-test odds given a positive test, while the corresponding post-test odds were decreased by 52% given a negative test (sensitivity and specificity of 0.66 and 0.70, respectively). In rank order, the following variables had the largest impact on prediction performance: neck circumference, body mass index, age, snoring frequency, waist circumference, and snoring loudness.
Keywords: Age Factors; Aged; Algorithms; Body Mass Index; Cohort Studies; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Risk Factors; ROC Curve; Sleep Apnea Syndromes; Snoring; Waist Circumference

Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. - Smith, Nicholas L; Chen, Ming-Huei; Dehghan, Abbas; Strachan, David P; Basu, Saonli; Soranzo, Nicole; Hayward, Caroline; Rudan, Igor; Sabater-Lleal, Maria; Bis, Joshua C; de Maat, Moniek P M; Rumley, Ann; et al. (Circulation, 2010)
BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
Keywords: Adult; Factor VII; Factor VIII; Female; Genome-Wide Association Study; Hemostasis; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Thrombosis; von Willebrand Factor

Obesity is linked with lower brain volume in 700 AD and MCI patients. - Ho, April J; Raji, Cyrus A; Becker, James T; Lopez, Oscar L; Kuller, Lewis H; Hua, Xue; Lee, Suh; Hibar, Derrek; Dinov, Ivo D; Stein, Jason L; Jack, Clifford R; Weiner, Michael W; et al. (Neurobiol Aging, 2010)
Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Body Mass Index; Brain; Cognition Disorders; Cohort Studies; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Obesity; Organ Size; Prospective Studies; Risk Factors

Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. - Redline, Susan; Yenokyan, Gayane; Gottlieb, Daniel J; Shahar, Eyal; O'Connor, George T; Resnick, Helaine E; Diener-West, Marie; Sanders, Mark H; Wolf, Philip A; Geraghty, Estella M; Ali, Tauqeer; Lebowitz, Michael; et al. (Am J Respir Crit Care Med, 2010)
RATIONALE: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population. OBJECTIVES: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. METHODS: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke. MEASUREMENTS AND MAIN RESULTS: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. CONCLUSIONS: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
Keywords: Aged; Female; Humans; Longitudinal Studies; Male; Middle Aged; Polysomnography; Proportional Hazards Models; Prospective Studies; Severity of Illness Index; Sex Factors; Sleep Apnea, Obstructive; Stroke

Parity and the association with diabetes in older women. - Fowler-Brown, Angela G; de Boer, Ian H; Catov, Janet M; Carnethon, Mercedes R; Kamineni, Aruna; Kuller, Lewis H; Siscovick, David S; Mukamal, Kenneth J (Diabetes Care, 2010)
OBJECTIVE: To examine the relationship of parity with diabetes and markers of glucose homeostasis in older women. RESEARCH DESIGN AND METHODS: We used data from the female participants in the Cardiovascular Health Study, a longitudinal cohort of adults aged >or=65 years. These data included an assessment of parity (baseline) and fasting serum levels of glucose, insulin, and medication use (baseline and follow-up). We estimated both the cross-sectional relationship of parity with baseline diabetes and the relationship of parity with incident diabetes. RESULTS: In unadjusted analyses, women with grand multiparity (>or=5 live births) had a higher prevalence of diabetes at baseline compared with those with fewer births and with nulliparous women (25 vs. 12 vs. 15%; P < 0.001). In regression models controlling for age and race, grand multiparity was associated with increased prevalence of diabetes (prevalence ratio 1.57 [95% CI 1.20-2.06]); with addition of demographic and clinical factors to the model, the association was attenuated (1.33 [1.00-1.77]). In final models that included body anthropometrics, the association was no longer significant (1.21 [0.86-1.49]). In those without diabetes at baseline, parity was not associated with incident diabetes or with fasting glucose; however, there was a modest association of parity with fasting insulin and homeostasis assessment model of insulin resistance. CONCLUSIONS: Grand multiparity is associated with diabetes in elderly women in cross-sectional analyses. This relationship seems to be confounded and/or mediated by variation in body weight and sociodemographic factors by parity status. In older nondiabetic women, higher parity does not pose an ongoing risk of developing diabetes.
Keywords: Aged; Body Weight; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Parity; Pregnancy; Socioeconomic Factors

Physical activity and years of healthy life in older adults: results from the cardiovascular health study. - Hirsch, Calvin H; Diehr, Paula; Newman, Anne B; Gerrior, Shirley A; Pratt, Charlotte; Lebowitz, Michael D; Jackson, Sharon A (J Aging Phys Act, 2010)
Little is known about how many years of life and disability-free years seniors can gain through exercise. Using data from the Cardiovascular Health Study, the authors estimated the extra years of life and self-reported healthy life (over 11 years) and years without impairment in activities of daily living (over 6 years) associated with quintiles of physical activity (PA) in older adults from different age groups. They estimated PA from the Minnesota Leisure Time Activities Questionnaire. Multivariable linear regression adjusted for health-related covariates. The relative gains in survival and years of healthy life (YHL) generally were proportionate to the amount of PA, greater among those 75+, and higher in men. Compared with being sedentary, the most active men 75+ had 1.49 more YHL (95% CI: 0.79, 2.19), and the most active women 75+ had 1.06 more YHL (95% CI: 0.44, 1.68). Seniors over age 74 experience the largest relative gains in survival and healthy life from physical activity.
Keywords: Activities of Daily Living; Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Exercise; Female; Health Behavior; Health Status; Humans; Leisure Activities; Life Style; Male; Quality-Adjusted Life Years; Sex Factors

Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. - Erickson, K I; Raji, C A; Lopez, O L; Becker, J T; Rosano, C; Newman, A B; Gach, H M; Thompson, P M; Ho, A J; Kuller, L H (Neurology, 2010)
OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
Keywords: Aged; Aged, 80 and over; Brain; Brain Mapping; Cardiovascular Diseases; Cognition Disorders; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Motor Activity; Neuropsychological Tests; Odds Ratio; Predictive Value of Tests; Surveys and Questionnaires

Polymorphisms in the mitochondrial DNA control region and frailty in older adults. - Moore, Ann Z; Biggs, Mary L; Matteini, Amy; O'Connor, Ashley; McGuire, Sarah; Beamer, Brock A; Fallin, M Danielle; Fried, Linda P; Walston, Jeremy; Chakravarti, Aravinda; Arking, Dan E (PLoS One, 2010)
BACKGROUND: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults. METHODOLOGY/PRINCIPAL FINDINGS: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002). CONCLUSIONS: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
Keywords: Aged; Aged, 80 and over; DNA, Mitochondrial; Female; Frail Elderly; Genotype; Humans; Male; Polymorphism, Genetic

Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study. - Ton, T G; Jain, S; Boudreau, R; Thacker, E L; Strotmeyer, E S; Newman, A B; Longstreth, W T; Checkoway, H (Neuroepidemiology, 2010)
BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis. METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD. RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null. CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.
Keywords: Aged; Aged, 80 and over; Cardiovascular System; Cohort Studies; Female; Health Status; Humans; Incidence; Male; Odds Ratio; Parkinson Disease; Prevalence; Prospective Studies; Risk Factors; Smoking; Surveys and Questionnaires; United States

Prevalence, incidence, and persistence of major depressive symptoms in the Cardiovascular Health Study. - Thielke, Stephen M; Diehr, Paula; Unutzer, Jurgen (Aging Ment Health, 2010)
PURPOSE: To explore the association of major depressive symptoms with advancing age, sex, and self-rated health among older adults. DESIGN AND METHODS: We analyzed 10 years of annual assessments in a longitudinal cohort of 5888 Medicare recipients in the Cardiovascular Health Study. Self-rated health was assessed with a single question, and subjects categorized as healthy or sick. Major depressive symptoms were assessed using the Center for Epidemiologic Studies Short Depression Scale, with subjects categorized as nondepressed (score < 10) or depressed (> or =10). Age-, sex-, and health-specific prevalence of depression and the probabilities of transition between depressed and nondepressed states were estimated. RESULTS: The prevalence of a major depressive state was higher in women, and increased with advancing age. The probability of becoming depressed increased with advancing age among the healthy but not the sick. Women showed a greater probability than men of becoming depressed, regardless of health status. Major depressive symptoms persisted over one-year intervals in about 60% of the healthy and 75% of the sick, with little difference between men and women. IMPLICATIONS: Clinically significant depressive symptoms occur commonly in older adults, especially women, increase with advancing age, are associated with poor self-rated health, and are largely intransigent. In order to limit the deleterious consequences of depression among older adults, increased attention to prevention, screening, and treatment is warranted. A self-rated health item could be used in clinical settings to refine the prognosis of late-life depression.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Cohort Studies; Depression; Depressive Disorder, Major; Female; Geriatric Assessment; Health Status; Humans; Incidence; Longitudinal Studies; Male; Personality Assessment; Prevalence; Psychiatric Status Rating Scales; Quality of Life; Sex Factors; Surveys and Questionnaires

Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. - de Weerd, Marjolein; Greving, Jacoba P; Hedblad, Bo; Lorenz, Matthias W; Mathiesen, Ellisiv B; O'Leary, Daniel H; Rosvall, Maria; Sitzer, Matthias; Buskens, Erik; Bots, Michiel L (Stroke, 2010)
BACKGROUND AND PURPOSE: In the discussion on the cost-effectiveness of screening, precise estimates of severe asymptomatic carotid stenosis are vital. Accordingly, we assessed the prevalence of moderate and severe asymptomatic carotid stenosis by age and sex using pooled cohort data. METHODS: We performed an individual participant data meta-analysis (23 706 participants) of 4 population-based studies (Malmö Diet and Cancer Study, Tromsø, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study). Outcomes of interest were asymptomatic moderate (> or =50%) and severe carotid stenosis (> or =70%). RESULTS: Prevalence of moderate asymptomatic carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged > or =80 years. For women, this prevalence increased from 0% (0% to 0.2%) to 5.0% (3.1% to 7.5%). Prevalence of severe asymptomatic carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged > or =80. For women, this prevalence increased from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%). CONCLUSIONS: The prevalence of severe asymptomatic carotid stenosis in the general population ranges from 0% to 3.1%, which is useful information in the discussion on the cost-effectiveness of screening.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Carotid Stenosis; Female; Humans; Male; Mass Screening; Middle Aged; Prevalence; Severity of Illness Index; Sex Factors

Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. - Gottlieb, Daniel J; Yenokyan, Gayane; Newman, Anne B; O'Connor, George T; Punjabi, Naresh M; Quan, Stuart F; Redline, Susan; Resnick, Helaine E; Tong, Elisa K; Diener-West, Marie; Shahar, Eyal (Circulation, 2010)
BACKGROUND: Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women. METHODS AND RESULTS: A total of 1927 men and 2495 women > or =40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men < or =70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI > or =30 were 68% more likely to develop coronary heart disease than those with AHI <5. Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI > or =30 were 58% more likely to develop heart failure than those with AHI <5. CONCLUSIONS: Obstructive sleep apnea is associated with an increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.
Keywords: Adult; Aged; Coronary Disease; Female; Heart Failure; Humans; Longitudinal Studies; Male; Middle Aged; Polysomnography; Proportional Hazards Models; Prospective Studies; Sleep Apnea, Obstructive; Survival Analysis

Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. - Ohira, Tetsuya; Folsom, Aaron R; Cushman, Mary; White, Richard H; Hannan, Peter J; Rosamond, Wayne D; Heckbert, Susan R (Br J Haematol, 2010)
Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% confidence interval [CI], 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.
Keywords: Age Factors; Aged; Epidemiologic Methods; Estrogen Replacement Therapy; Female; Humans; Male; Middle Aged; Parity; Pregnancy; Reproductive History; United States; Venous Thromboembolism

Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. - Barnes, Deborah E; Haight, Thaddeus J; Mehta, Kala M; Carlson, Michelle C; Kuller, Lewis H; Tager, Ira B (Am J Epidemiol, 2010)
Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16-25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0-15 years) SHS exposure and < or =25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.
Keywords: Aged; Dementia; Female; Humans; Incidence; Male; Risk Factors; Tobacco Smoke Pollution; Vascular Diseases

Serum albumin and risk of venous thromboembolism. - Folsom, Aaron R; Lutsey, Pamela L; Heckbert, Susan R; Cushman, Mary (Thromb Haemost, 2010)
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
Keywords: Aged; Biomarkers; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Risk Factors; Serum Albumin; United States; Venous Thromboembolism

Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. - Buxbaum, Joel; Alexander, Alice; Koziol, James; Tagoe, Clement; Fox, Ervin; Kitzman, Dalane (Am Heart J, 2010)
BACKGROUND: Many African Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after the age of 65 years. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African Americans. METHODS: Five thousand consenting African Americans, aged 41 to 93 years, in 2 community studies of cardiovascular risk (CHS and ARIC) were included in the study. The following were performed: genotyping of banked DNA for TTR V122I allele status and review of cardiovascular and demographic parameters in CHS and ARIC databases, with statistical comparisons of the frequency of congestive heart failure, survival, and occurrence of features of cardiac amyloidosis in carriers of the amyloidogenic allele and controls. RESULTS: One hundred nineteen (3.23%) of 3,712 ARIC and 17 (2.12%) of 805 CHS African Americans carried TTR V122I. After the age of 65 years (CHS), the frequencies of congestive heart failure (38% vs 15%, relative risk 2.62, P = .04) and mortality (76% vs 53%, relative risk 1.46, P = .08) were higher in V122I allele carriers than in age-, gender- and ethnically matched controls. In ARIC (all subjects <65 years old), there were no differences between carriers and noncarriers in mortality, frequency of congestive heart failure, or findings consistent with cardiac amyloidosis. CONCLUSIONS: Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community-dwelling African Americans. Before the age of 65 years, the allele has no discernible impact on cardiac function or mortality. After the age of 70 years, carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age-dependent clinical penetrance of this autosomal dominant gene.
Keywords: Adult; African Americans; Aged; Aged, 80 and over; Amyloidosis; Female; Gene Frequency; Heart Diseases; Humans; Isoleucine; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Prealbumin; Ultrasonography; Valine

Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study. - Baldwin, Carol M; Ervin, Ann-Margret; Mays, Mary Z; Robbins, John; Shafazand, Shirin; Walsleben, Joyce; Weaver, Terri (J Clin Sleep Med, 2010)
STUDY OBJECTIVES: To compare health-related quality of life (HR-QOL) across subgroups defined by sleep disturbances and ethnicity. METHODS: Men (47%) and women (53%) Sleep Heart Health Study participants age 40 and older (N = 5237) underwent overnight polysomnography and completed self-report questionnaires on symptoms of sleep disturbances. The physical and mental composite scales (PCS and MCS) of the Medical Outcomes Study 36-item short form survey assessed HR-QOL and were compared to sleep data. RESULTS: Participants self-identified as Caucasian/White (n = 4482, 86%), African American/Black (n = 490, 9%), or Hispanic/Mexican American (n = 265, 5%). The prevalence of obstructive sleep apnea (OSA) was 17%, frequent snoring was 34%, difficulty initiating or maintaining sleep (DIMS; insomnia symptoms) was 30%, and excessive daytime sleepiness (EDS) was 25%. African American participants with frequent snoring, insomnia symptoms, or EDS had significantly poorer physical health compared to Caucasians (p < 0.001). Hispanics with frequent snoring, insomnia symptoms, or EDS had significantly poorer mental health than Caucasian participants (p <0.001). Neither PCS nor MCS scores differed significantly across ethnic subgroups for participants with moderate to severe OSA (respiratory disturbance index > 15, 4% desaturation). CONCLUSIONS: Across ethnic/racial subgroups, sleep disturbances are associated with worse physical and better mental HR-QOL than the U.S. norm, but this relationship may be moderated by comorbid health conditions. This study replicates and extends prior research indicating differences among minority and non-minority participants and highlights the need for future studies of sleep disturbances with larger samples of minorities that control for comorbid health conditions.
Keywords: African Americans; Cohort Studies; Ethnic Groups; European Continental Ancestry Group; Female; Health Status; Heart Diseases; Hispanic Americans; Humans; Longitudinal Studies; Male; Mental Health; Middle Aged; Polysomnography; Prevalence; Quality of Life; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Snoring; Surveys and Questionnaires; United States

Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. - Chami, Hassan A; Baldwin, Carol M; Silverman, Angela; Zhang, Ying; Rapoport, David; Punjabi, Naresh M; Gottlieb, Daniel J (Am J Respir Crit Care Med, 2010)
RATIONALE: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain. OBJECTIVE: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort. METHODS: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6% women, 22.6% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHI(REM)) and non-REM (AHI(NREM)) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36. MEASUREMENTS AND MAIN RESULTS: AHI(REM) was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHI(NREM) x AHI(REM) was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHI(NREM) was associated with the ESS score (beta = 0.25; 95% confidence interval [CI], 0.16 to 0.34) and the physical (beta = -0.12; 95% CI, -0.42 to -0.01) and mental (beta = -0.20; 95% CI, -0.20 to -0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHI(REM). CONCLUSIONS: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.
Keywords: Aged; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Polysomnography; Quality of Life; Sleep; Sleep Apnea Syndromes; Sleep, REM

Study of the relationship between the interleukin-6 gene and obstructive sleep apnea. - Larkin, Emma K; Patel, Sanjay R; Zhu, Xiaofeng; Tracy, Russell P; Jenny, Nancy S; Reiner, Alex P; Walston, Jeremy; Redline, Susan (Clin Transl Sci, 2010)
Keywords: Adult; African Americans; Alleles; Female; Humans; Interleukin-6; Male; Middle Aged; Polymorphism, Single Nucleotide; Sleep Apnea, Obstructive

Subclinical hypothyroidism and the risk of coronary heart disease and mortality. - Rodondi, Nicolas; den Elzen, Wendy P J; Bauer, Douglas C; Cappola, Anne R; Razvi, Salman; Walsh, John P; Asvold, Bjørn O; Iervasi, Giorgio; Imaizumi, Misa; Collet, Tinh-Hai; Bremner, Alexandra; Maisonneuve, Patrick; et al. (JAMA, 2010)
CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease. OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Disease; Female; Humans; Hypothyroidism; Male; Middle Aged; Mortality; Prospective Studies; Risk; Thyrotropin; Young Adult

Subclinical thyroid dysfunction and incident hip fracture in older adults. - Lee, Jennifer S; Bůzková, Petra; Fink, Howard A; Vu, Joseph; Carbone, Laura; Chen, Zhao; Cauley, Jane; Bauer, Doug C; Cappola, Anne R; Robbins, John (Arch Intern Med, 2010)
BACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture. METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline. RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women. CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.
Keywords: Aged; Female; Follow-Up Studies; Hip Fractures; Humans; Hyperthyroidism; Hypothyroidism; Incidence; Male; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Distribution; Thyrotropin; United States

Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. - Mozaffarian, Dariush; Cao, Haiming; King, Irena B; Lemaitre, Rozenn N; Song, Xiaoling; Siscovick, David S; Hotamisligil, Gökhan S (Ann Intern Med, 2010)
BACKGROUND: Palmitoleic acid (cis-16:1n-7), which is produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative. OBJECTIVE: To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes. DESIGN: Prospective cohort study from 1992 to 2006. SETTING: Four U.S. communities. PATIENTS: 3736 adults in the Cardiovascular Health Study. MEASUREMENTS: Anthropometric characteristics and levels of plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose-insulin measured at baseline in 1992 and dietary habits measured 3 years earlier. Multivariate-adjusted models were used to investigate how demographic, clinical, and lifestyle factors independently related to plasma phospholipid trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). Findings were validated for metabolic risk factors in an independent cohort of 327 women. RESULTS: In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels (1.9% across quintiles; P = 0.040), lower triglyceride levels (-19.0%; P < 0.001), a lower total cholesterol-HDL cholesterol ratio (-4.7%; P < 0.001), lower C-reactive protein levels (-13.8%; P = 0.05), and lower insulin resistance (-16.7%, P < 0.001). Trans-palmitoleate was also associated with a substantially lower incidence of diabetes, with multivariate hazard ratios of 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5 versus quintile 1 (P for trend < 0.001). Findings were independent of estimated dairy consumption or other fatty acid dairy biomarkers. Protective associations with metabolic risk factors were confirmed in the validation cohort. LIMITATION: Results could be affected by measurement error or residual confounding. CONCLUSION: Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
Keywords: Adiposity; Aged; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Dairy Products; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Feeding Behavior; Female; Humans; Incidence; Insulin Resistance; Male; Prospective Studies; Risk Factors; Triglycerides; United States

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. - Sarwar, Nadeem; Sandhu, Manjinder S; Ricketts, Sally L; Butterworth, Adam S; Di Angelantonio, Emanuele; Boekholdt, S Matthijs; Ouwehand, Willem; Watkins, Hugh; Samani, Nilesh J; Saleheen, Danish; Lawlor, Debbie; Reilly, Muredach P; et al. (Lancet, 2010)
BACKGROUND: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. METHODS: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. FINDINGS: The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. INTERPRETATION: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. FUNDING: British Heart Foundation, UK Medical Research Council, Novartis.
Keywords: Apolipoprotein A-V; Apolipoproteins; Apolipoproteins A; Coronary Disease; Gene Frequency; Genotype; Humans; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Mendelian Randomization Analysis; Particle Size; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors; Triglycerides

Utility of sleep stage transitions in assessing sleep continuity. - Laffan, Alison; Caffo, Brian; Swihart, Bruce J; Punjabi, Naresh M (Sleep, 2010)
STUDY OBJECTIVES: Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics. DESIGN AND SETTING: Analysis of the Sleep Heart Health Study polysomnographic data. PARTICIPANTS: A community cohort. MEASUREMENTS AND RESULTS: Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (<7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77-10.10 events/h), third (10.11-13.34 events/h), and fourth (≥13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep. CONCLUSIONS: Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.
Keywords: Age Factors; Aged; Arousal; Body Mass Index; Cohort Studies; Female; Humans; Male; Middle Aged; Polysomnography; Predictive Value of Tests; Risk Factors; Sex Factors; Sleep Stages; Sleep Wake Disorders

Validation of an atrial fibrillation risk algorithm in whites and African Americans. - Schnabel, Renate B; Aspelund, Thor; Li, Guo; Sullivan, Lisa M; Suchy-Dicey, Astrid; Harris, Tamara B; Pencina, Michael J; D'Agostino, Ralph B; Levy, Daniel; Kannel, William B; Wang, Thomas J; Kronmal, Richard A; et al. (Arch Intern Med, 2010)
BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups. METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure. RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk. CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.
Keywords: African Continental Ancestry Group; Age Factors; Aged; Aged, 80 and over; Algorithms; Atrial Fibrillation; Blood Pressure; Body Mass Index; Cohort Studies; Electrocardiography; Europe; European Continental Ancestry Group; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Sex Factors; Systole; United States

Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. - Kalogeropoulos, Andreas; Psaty, Bruce M; Vasan, Ramachandran S; Georgiopoulou, Vasiliki; Smith, Andrew L; Smith, Nicholas L; Kritchevsky, Stephen B; Wilson, Peter W F; Newman, Anne B; Harris, Tamara B; Butler, Javed (Circ Heart Fail, 2010)
BACKGROUND: The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model. METHODS AND RESULTS: Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow chi(2) was 14.72 (degrees of freedom, 10; P=0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results. CONCLUSIONS: The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.
Keywords: Age Distribution; Aged; Aged, 80 and over; Cause of Death; Cohort Studies; Confidence Intervals; Disease Progression; Echocardiography, Doppler; Female; Heart Failure; Humans; Incidence; Male; Models, Statistical; Predictive Value of Tests; Prognosis; Severity of Illness Index; Sex Distribution; Survival Analysis; United States

Antihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis. - Odden, Michelle C; Tager, Ira B; van der Laan, Mark J; Delaney, Joseph A C; Peralta, Carmen A; Katz, Ronit; Sarnak, Mark J; Psaty, Bruce M; Shlipak, Michael G (Int J Biostat, 2011)
BACKGROUND: The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model. METHODS: Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989-1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring. RESULTS: The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m(2). In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m(2) per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (-0.13, 4.59) ml/min/1.73 m(2) per year slower decline in eGFR. CONCLUSION: In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
Keywords: Aged; Antihypertensive Agents; Cystatin C; Data Interpretation, Statistical; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Longitudinal Studies; Male; Models, Statistical

Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study. - Rodriguez, Carlos J; Bartz, Traci M; Longstreth, W T; Kizer, Jorge R; Barasch, Eddy; Lloyd-Jones, Donald M; Gottdiener, John S (J Am Coll Cardiol, 2011)
OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts. BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke. METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995). RESULTS: The mean age of the participants was 74.5 ± 4.8 years, and 39.3% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings. CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.
Keywords: Aged; Aortic Valve Stenosis; Brain; Brain Infarction; Calcinosis; Cohort Studies; Female; Humans; Magnetic Resonance Imaging; Male; Mitral Valve Stenosis; Retrospective Studies

Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study. - Ix, Joachim H; Biggs, Mary L; Kizer, Jorge R; Mukamal, Kenneth J; Djoussé, Luc; Zieman, Susan J; de Boer, Ian H; Nelson, Tracy L; Newman, Anne B; Criqui, Michael H; Siscovick, David S (Am J Epidemiol, 2011)
The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥ 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.
Keywords: Aged; Ankle Brachial Index; Body Mass Index; Cross-Sectional Studies; Health Status; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Obesity; Peripheral Arterial Disease; Prevalence; Sex Factors; Smoking; United States

Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study. - Zakai, N A; Lange, L; Longstreth, W T; O'Meara, E S; Kelley, J L; Fornage, M; Nikerson, D; Cushman, M; Reiner, A P (J Thromb Haemost, 2011)
BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive. OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged ≥ 65 years of the observational Cardiovascular Health Study cohort. PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke. RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 × 10(-83)) and rs3093261 (β = 2.99, P = 3.93 × 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels. CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.
Keywords: Blood Coagulation Factors; Cardiovascular Diseases; Cohort Studies; Factor VII; Female; Humans; Inflammation; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Stroke

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. - Böger, Carsten A; Gorski, Mathias; Li, Man; Hoffmann, Michael M; Huang, Chunmei; Yang, Qiong; Teumer, Alexander; Krane, Vera; O'Seaghdha, Conall M; Kutalik, Zoltán; Wichmann, H-Erich; Haak, Thomas; et al. (PLoS Genet, 2011)
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Keywords: Adaptor Proteins, Signal Transducing; Adult; Aged; Chronic Disease; Creatinine; European Continental Ancestry Group; Female; Follow-Up Studies; Genetic Association Studies; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Epidermal Growth Factor; Uromodulin

Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. - Franceschini, Nora; Carty, Cara; Bůzková, Petra; Reiner, Alex P; Garrett, Tiana; Lin, Yi; Vöckler, Jens-S; Hindorff, Lucia A; Cole, Shelley A; Boerwinkle, Eric; Lin, Dan-Yu; Bookman, Ebony; et al. (Circ Cardiovasc Genet, 2011)
BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities. CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
Keywords: Aged; Aged, 80 and over; Continental Population Groups; Coronary Disease; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies

The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study. - Benke, K S; Carlson, M C; Doan, B Q; Walston, J D; Xue, Q L; Reiner, A P; Fried, L P; Arking, D E; Chakravarti, A; Fallin, M D (Exp Gerontol, 2011)
The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer's, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.
Keywords: African Americans; Aged; Aged, 80 and over; Cognition; Cognition Disorders; Dementia; Educational Status; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-1beta; Linkage Disequilibrium; Longitudinal Studies; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; United States

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. - Fox, Ervin R; Young, J Hunter; Li, Yali; Dreisbach, Albert W; Keating, Brendan J; Musani, Solomon K; Liu, Kiang; Morrison, Alanna C; Ganesh, Santhi; Kutlar, Abdullah; Ramachandran, Vasan S; Polak, Josef F; et al. (Hum Mol Genet, 2011)
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
Keywords: Adult; African Americans; Aged; Blood Pressure; Cohort Studies; Diastole; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Hypertension; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Systole

Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). - Wassel, Christina L; Lange, Leslie A; Keating, Brendan J; Taylor, Kira C; Johnson, Andrew D; Palmer, Cameron; Ho, Lindsey A; Smith, Nicholas L; Lange, Ethan M; Li, Yun; Yang, Qiong; Delaney, Joseph A; et al. (Blood, 2011)
Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.
Keywords: Adult; African Americans; Aged; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Fibrinogen; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors

Association of HSP70 and its co-chaperones with Alzheimer's disease. - Broer, Linda; Ikram, Mohammad Arfan; Schuur, Maaike; DeStefano, Anita L; Bis, Joshua C; Liu, Fan; Rivadeneira, Fernando; Uitterlinden, André G; Beiser, Alexa S; Longstreth, William T; Hofman, Albert; Aulchenko, Yurii; et al. (J Alzheimers Dis, 2011)
The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Genetic Association Studies; Genetic Variation; HSP70 Heat-Shock Proteins; Humans; Middle Aged; Molecular Chaperones; Polymorphism, Single Nucleotide

Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. - Johnson, Andrew D; Newton-Cheh, Christopher; Chasman, Daniel I; Ehret, Georg B; Johnson, Toby; Rose, Lynda; Rice, Kenneth; Verwoert, Germaine C; Launer, Lenore J; Gudnason, Vilmundur; Larson, Martin G; Chakravarti, Aravinda; et al. (Hypertension, 2011)
We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.
Keywords: Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-1

Association of incident cardiovascular disease with progression of sleep-disordered breathing. - Chami, Hassan A; Resnick, Helaine E; Quan, Stuart F; Gottlieb, Daniel J (Circulation, 2011)
BACKGROUND: Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied. METHODS AND RESULTS: A total of 2721 Sleep Heart Health Study participants (mean age 62, standard deviation=10 years; 57% women; 23% minority) without CVD at baseline underwent 2 polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure, and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index between the 2 polysomnograms was tested with general linear models, with adjustment for age, sex, race, study center, history of diabetes mellitus, change in body mass index, change in neck circumference, percent sleep time spent in supine sleep, and time between the 2 polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared with participants without incident CVD, those with incident CVD experienced larger increases in apnea-hypopnea index between polysomnograms. The difference in adjusted mean apnea-hypopnea index change between subjects with and without incident CVD was 2.75 events per hour (95% confidence interval, 0.26 to 5.24; P=0.032). This association persisted after subjects with central sleep apnea were excluded. Compared with participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95% confidence interval, 0.10 to 1.75; P=0.04) and by 1.07 events per hour (95% confidence interval, 0.40 to 1.74; P=0.001), respectively. CONCLUSIONS: In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.
Keywords: Aged; Cardiovascular Diseases; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Polysomnography; Risk Factors; Sleep Apnea Syndromes