Rare genetic variants explain missing heritability in smoking. - Jang, Seon-Kyeong; Evans, Luke; Fialkowski, Allison; Arnett, Donna K; Ashley-Koch, Allison E; Barnes, Kathleen C; Becker, Diane M; Bis, Joshua C; Blangero, John; Bleecker, Eugene R; Boorgula, Meher Preethi; Bowden, Donald W; et al. (Nat Hum Behav, 2022)
Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Relation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study). - Gottdiener, John S; Bůzková, Petra; Kahn, Peter A; DeFilippi, Christopher; Shah, Sanjiv; Barasch, Eddy; Kizer, Jorge R; Psaty, Bruce; Gardin, Julius M (Am J Cardiol, 2022)
Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

{Replication study of AD-associated rare variants - Neupane, A.; Lenny, B.; Budde, J. P.; Wang, F.; Norton, J.; Morris, J. C.; Cruchaga, C.; Fernández, M. V. (Alzheimers Dement, 2022)

{A saturated map of common genetic variants associated with human height - Yengo, L.; Vedantam, S.; Marouli, E.; Sidorenko, J.; Bartell, E.; Sakaue, S.; Graff, M.; Eliasen, A. U.; Jiang, Y.; Raghavan, S.; Miao, J.; Arias, J. D.; et al. (Nature, 2022)
) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. - Gao, Hans; Patel, Sheena; Fohtung, Raymond B; Cawthon, Peggy M; Newman, Anne B; Cauley, Jane A; Carbone, Laura; Chaves, Paulo H M; Stein, Phyllis K; Civitelli, Roberto; Kizer, Jorge R (J Am Geriatr Soc, 2022)
BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent. METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC. RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men. CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS). - Sillah, Arthur; Watson, Nathaniel F; Peters, Ulrike; Biggs, Mary L; Nieto, F Javier; Li, Christopher I; Gozal, David; Thornton, Timothy; Barrie, Sonnah; Phipps, Amanda I (Cancer Epidemiol, 2022)
BACKGROUND: Sleep problems (SP) can indicate underlying sleep disorders, such as obstructive sleep apnea, which may adversely impact cancer risk and mortality. METHODS: We assessed the association of baseline and longitudinal sleep apnea and insomnia symptoms with incident cancer (N = 3930) and cancer mortality (N = 4580) in the Cardiovascular Health Study. We used Cox proportional hazards regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the associations. RESULTS: Overall, 885 incident cancers and 804 cancer deaths were identified over a median follow-up of 12 and 14 years, respectively. Compared to participants who reported no sleep apnea symptoms, the risk of incident cancer was inversely associated [(HR (95%CI)] with snoring [0.84 (0.71, 0.99)]. We noted an elevated prostate cancer incidence for apnea [2.34 (1.32, 4.15)] and snoring [1.69 (1.11, 2.57)]. We also noted an elevated HR for lymphatic or hematopoietic cancers [daytime sleepiness: 1.81 (1.06, 3.08)]. We found an inverse relationship for cancer mortality with respect to snoring [0.73 (0.62, 0.8)] and apnea [(0.69 (0.51, 0.94))]. We noted a significant inverse relationship between difficulty falling asleep and colorectal cancer death [0.32 (0.15, 0.69)] and snoring with lung cancer death [0.56 (0.35, 0.89)]. CONCLUSIONS: The relationship between SP and cancer risk and mortality was heterogeneous. Larger prospective studies addressing more cancer sites, molecular type-specific associations, and better longitudinal SP assessments are needed for improved delineation of SP-cancer risk dyad.

Stroke genetics informs drug discovery and risk prediction across ancestries. - Mishra, Aniket; Malik, Rainer; Hachiya, Tsuyoshi; Jürgenson, Tuuli; Namba, Shinichi; Posner, Daniel C; Kamanu, Frederick K; Koido, Masaru; Le Grand, Quentin; Shi, Mingyang; He, Yunye; Georgakis, Marios K; et al. (Nature, 2022)
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. - Liang, Jingjing; Wang, Heming; Cade, Brian E; Kurniansyah, Nuzulul; He, Karen Y; Lee, Jiwon; Sands, Scott A; Brody, Jennifer; Chen, Han; Gottlieb, Daniel J; Evans, Daniel S; Guo, Xiuqing; et al. (Am J Respir Crit Care Med, 2022)
INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes. METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007). CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

{Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE) - Lai, H. T. M.; Imamura, F.; Korat, A. V. A.; Murphy, R. A.; Tintle, N.; Bassett, J. K.; Chen, J.; ger, J.; Chien, K. L.; Senn, M.; Wood, A. C.; Forouhi, N. G.; et al. (Diabetes Care, 2022)
Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.\ 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.\ 0.1).\ Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.

Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study. - Elam, Rachel E; Bůzková, Petra; Barzilay, Joshua I; Wang, Zeneng; Nemet, Ina; Budoff, Matthew J; Cauley, Jane A; Fink, Howard A; Lee, Yujin; Robbins, John A; Wang, Meng; Hazen, Stanley L; et al. (Bone, 2022)
CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain. OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults. DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study. PARTICIPANTS: 5019 U.S. adults aged ≥65 years. EXPOSURE: Plasma TMAO. MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400). RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight. CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.
Keywords: Absorptiometry, Photon; Aged; Bone Density; Female; Hip Fractures; Humans; Male; Methylamines; Risk Factors

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. - Wang, Zhe; Choi, Shing Wan; Chami, Nathalie; Boerwinkle, Eric; Fornage, Myriam; Redline, Susan; Bis, Joshua C; Brody, Jennifer A; Psaty, Bruce M; Kim, Wonji; McDonald, Merry-Lynn N; Regan, Elizabeth A; et al. (Front Endocrinol (Lausanne), 2022)
Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.
Keywords: Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Obesity; Whole Genome Sequencing

Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. - Pankratz, Nathan; Wei, Peng; Brody, Jennifer A; Chen, Ming-Huei; Vries, Paul S; Huffman, Jennifer E; Stimson, Mary Rachel; Auer, Paul L; Boerwinkle, Eric; Cushman, Mary; Maat, Moniek P M; Folsom, Aaron R; et al. (Hum Mol Genet, 2022)
Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. - DiCorpo, Daniel; Gaynor, Sheila M; Russell, Emily M; Westerman, Kenneth E; Raffield, Laura M; Majarian, Timothy D; Wu, Peitao; Sarnowski, Chloe; Highland, Heather M; Jackson, Anne; Hasbani, Natalie R; de Vries, Paul S; et al. (Commun Biol, 2022)
The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
Keywords: Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Insulin; National Heart, Lung, and Blood Institute (U.S.); Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Precision Medicine; Receptors, Immunologic; United States

Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. - Wheeler, Marsha M; Stilp, Adrienne M; Rao, Shuquan; Halldorsson, Bjarni V; Beyter, Doruk; Wen, Jia; Mihkaylova, Anna V; McHugh, Caitlin P; Lane, John; Jiang, Min-Zhi; Raffield, Laura M; Jun, Goo; et al. (Nat Commun, 2022)
Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
Keywords: Blood Cells; Genome-Wide Association Study; Humans; Whole Genome Sequencing

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. - Pan, Yang; Sun, Xiao; Mi, Xuenan; Huang, Zhijie; Hsu, Yenchih; Hixson, James E; Munzy, Donna; Metcalf, Ginger; Franceschini, Nora; Tin, Adrienne; Köttgen, Anna; Francis, Michael; et al. (Hum Mol Genet, 2022)
Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

{Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project - Hu, Y.; Haessler, J. W.; Manansala, R.; Wiggins, K. L.; Moscati, A.; Beiser, A.; Heard-Costa, N. L.; Sarnowski, C.; Raffield, L. M.; Chung, J.; Marini, S.; Anderson, C. D.; et al. (Stroke, 2022)
Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).\ Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.\ .\ We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. - Weinstock, Joshua S; Gopakumar, Jayakrishnan; Burugula, Bala Bharathi; Uddin, Md Mesbah; Jahn, Nikolaus; Belk, Julia A; Bouzid, Hind; Daniel, Bence; Miao, Zhuang; Ly, Nghi; Mack, Taralynn M; Luna, Sofia E; et al. (Nature, 2023)
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
Keywords: Alleles; Animals; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mutation; Promoter Regions, Genetic

Age-Related Factors Associated with Hip Fracture Risk. - Bůzková, Petra; Cauley, Jane A; Fink, Howard A; Robbins, John A; Mukamal, Kenneth J; Barzilay, Joshua I (Endocr Pract, 2023)
OBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied. METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up. RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture. CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.

Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study. - Yi, Jiayi; Wang, Lili; Guo, Xinli; Ren, Xiangpeng (J Transl Med, 2023)
BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence. METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD. RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD. CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.
Keywords: Atherosclerosis; Cardiovascular Diseases; Cohort Studies; Female; Heart Disease Risk Factors; Humans; Incidence; Male; Middle Aged; Prospective Studies; Risk Factors

Association Between Acute Myocardial Infarction and Cognition. - Johansen, Michelle C; Ye, Wen; Gross, Alden; Gottesman, Rebecca F; Han, Dehua; Whitney, Rachael; Briceño, Emily M; Giordani, Bruno J; Shore, Supriya; Elkind, Mitchell S V; Manly, Jennifer J; Sacco, Ralph L; et al. (JAMA Neurol, 2023)
IMPORTANCE: The magnitude of cognitive change after incident myocardial infarction (MI) is unclear. OBJECTIVE: To assess whether incident MI is associated with changes in cognitive function after adjusting for pre-MI cognitive trajectories. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adults without MI, dementia, or stroke and with complete covariates from the following US population-based cohort studies conducted from 1971 to 2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Data were analyzed from July 2021 to January 2022. EXPOSURES: Incident MI. MAIN OUTCOMES AND MEASURES: The main outcome was change in global cognition. Secondary outcomes were changes in memory and executive function. Outcomes were standardized as mean (SD) T scores of 50 (10); a 1-point difference represented a 0.1-SD difference in cognition. Linear mixed-effects models estimated changes in cognition at the time of MI (change in the intercept) and the rate of cognitive change over the years after MI (change in the slope), controlling for pre-MI cognitive trajectories and participant factors, with interaction terms for race and sex. RESULTS: The study included 30 465 adults (mean [SD] age, 64 [10] years; 56% female), of whom 1033 had 1 or more MI event, and 29 432 did not have an MI event. Median follow-up was 6.4 years (IQR, 4.9-19.7 years). Overall, incident MI was not associated with an acute decrease in global cognition (-0.18 points; 95% CI, -0.52 to 0.17 points), executive function (-0.17 points; 95% CI, -0.53 to 0.18 points), or memory (0.62 points; 95% CI, -0.07 to 1.31 points). However, individuals with incident MI vs those without MI demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21 to -0.10 points per year), memory (-0.13 points per year; 95% CI, -0.22 to -0.04 points per year), and executive function (-0.14 points per year; 95% CI, -0.20 to -0.08 points per year) over the years after MI compared with pre-MI slopes. The interaction analysis suggested that race and sex modified the degree of change in the decline in global cognition after MI (race × post-MI slope interaction term, P = .02; sex × post-MI slope interaction term, P = .04), with a smaller change in the decline over the years after MI in Black individuals than in White individuals (difference in slope change, 0.22 points per year; 95% CI, 0.04-0.40 points per year) and in females than in males (difference in slope change, 0.12 points per year; 95% CI, 0.01-0.23 points per year). CONCLUSIONS: This cohort study using pooled data from 6 cohort studies found that incident MI was not associated with a decrease in global cognition, memory, or executive function at the time of the event compared with no MI but was associated with faster declines in global cognition, memory, and executive function over time. These findings suggest that prevention of MI may be important for long-term brain health.

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. - Liu, Xue; Sun, Xianbang; Zhang, Yuankai; Jiang, Wenqing; Lai, Meng; Wiggins, Kerri L; Raffield, Laura M; Bielak, Lawrence F; Zhao, Wei; Pitsillides, Achilleas; Haessler, Jeffrey; Zheng, Yinan; et al. (J Am Heart Assoc, 2023)
Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Association of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study. - Zhang, Xiao; Sanders, Jason L; Boudreau, Robert M; Arnold, Alice M; Justice, Jamie N; Espeland, Mark A; Kuchel, George A; Barzilai, Nir; Kuller, Lewis H; Lopez, Oscar L; Kritchevsky, Stephen B; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2023)
BACKGROUND: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration. METHODS: A Biomarker Index (BI) was constructed in the Cardiovascular Health Study (N=3197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up. RESULTS: The hazard ratio (HR, 95% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7% and 22.0% in women and men, respectively. CONCLUSIONS: BI was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.

Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. - Sheets, Kerry M; Bůzková, Petra; Chen, Zhao; Carbone, Laura D; Cauley, Jane A; Barzilay, Joshua I; Starks, Jamie L; Miller, Lindsay M; Fink, Howard A (Osteoporos Int, 2023)
UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture. INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture. METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive). RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90). CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.
Keywords: Aged; Brain Infarction; Frailty; Hip Fractures; Humans; Prospective Studies; Risk Factors; White Matter

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. - Elam, Rachel E; Bůzková, Petra; Delaney, Joseph A C; Fink, Howard A; Barzilay, Joshua I; Carbone, Laura D; Saha, Rick; Robbins, John A; Mukamal, Kenneth J; Valderrábano, Rodrigo J; Psaty, Bruce M; Tracy, Russell P; et al. (Calcif Tissue Int, 2023)
In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. - Zhang, Yuankai; Liu, Xue; Wiggins, Kerri L; Kurniansyah, Nuzulul; Guo, Xiuqing; Rodrigue, Amanda L; Zhao, Wei; Yanek, Lisa R; Ratliff, Scott M; Pitsillides, Achilleas; Aguirre Patiño, Juan Sebastian; Sofer, Tamar; et al. (Neurology, 2023)
BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Association of Obesity With Cognitive Decline in Black and White Americans. - Quaye, Emmanuel; Galecki, Andrzej T; Tilton, Nicholas; Whitney, Rachael; Briceño, Emily M; Elkind, Mitchell S V; Fitzpatrick, Annette L; Gottesman, Rebecca F; Griswold, Michael; Gross, Alden L; Heckbert, Susan R; Hughes, Timothy M; et al. (Neurology, 2023)
BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts. METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15). RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34). DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.
Keywords: Aged; Black or African American; Cognition; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Obesity; Risk Factors; United States; White

Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. - Ong, Kwok Leung; Marklund, Matti; Huang, Liping; Rye, Kerry-Anne; Hui, Nicholas; Pan, Xiong-Fei; Rebholz, Casey M; Kim, Hyunju; Steffen, Lyn M; van Westing, Anniek C; Geleijnse, Johanna M; Hoogeveen, Ellen K; et al. (BMJ, 2023)
OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
Keywords: alpha-Linolenic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease. - Dron, Jacqueline S; Patel, Aniruddh P; Zhang, Yiyi; Jurgens, Sean J; Maamari, Dimitri J; Wang, Minxian; Boerwinkle, Eric; Morrison, Alanna C; de Vries, Paul S; Fornage, Myriam; Hou, Lifang; Lloyd-Jones, Donald M; et al. (JAMA Cardiol, 2023)
IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies. OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk. DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022. EXPOSURES: PTVs in APOB and PCSK9. MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD. RESULTS: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004). CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. - Zhang, Yiyi; Dron, Jacqueline S; Bellows, Brandon K; Khera, Amit V; Liu, Junxiu; Balte, Pallavi P; Oelsner, Elizabeth C; Amr, Sami Samir; Lebo, Matthew S; Nagy, Anna; Peloso, Gina M; Natarajan, Pradeep; et al. (Circulation, 2023)
Keywords: Coronary Disease; Genotype; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study. - Carbone, Laura; Bůzková, Petra; Fink, Howard A; Robbins, John A; Barzilay, Joshua I; Elam, Rachel E; Isales, Carlos (JBMR Plus, 2023)
Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

{Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors - Levine, D. A.; Chen, B.; Galecki, A. T.; Gross, A. L.; o, E. M.; Whitney, R. T.; Ploutz-Snyder, R. J.; Giordani, B. J.; Sussman, J. B.; Burke, J. F.; Lazar, R. M.; Howard, V. J.; et al. (JAMA Netw Open, 2023)
Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.\ To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.\ Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.\ Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.\ The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.\ .002) but not executive function or memory declines.\ In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.

The associations of markers of endothelial dysfunction with hip fracture risk. - Barzilay, Joshua I; Bůzková, Petra; Fink, Howard A; Cauley, Jane A; Carbone, Laura; Elam, Rachel; Robbins, John A; Stein, Phyllis; Sheets, Kerry; Jalal, Diana; Mukamal, Kenneth J (Arch Osteoporos, 2023)
UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them. PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.
Keywords: Aged; Forearm; Hip Fractures; Humans; Osteoporotic Fractures; Vascular Diseases

Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study. - Mehta, Rupal; Bůzková, Petra; Patel, Harnish; Cheng, Jeanette; Kizer, Jorge R; Gottdiener, John S; Psaty, Bruce; Khan, Sadiya S; Ix, Joachim H; Isakova, Tamara; Shlipak, Michael G; Bansal, Nisha; et al. (Kidney360, 2023)
BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown. METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years. RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR. CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. - Georgakis, Marios K; Malik, Rainer; Hasbani, Natalie R; Shakt, Gabrielle; Morrison, Alanna C; Tsao, Noah L; Judy, Renae; Mitchell, Braxton D; Xu, Huichun; Montasser, May E; Do, Ron; Kenny, Eimear E; et al. (medRxiv, 2023)
BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease. METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated. RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants. CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

CHARGE-AF: A Useful Score For Atrial Fibrillation Prediction? - Goudis, Christos; Daios, Stylianos; Dimitriadis, Fotios; Liu, Tong (Curr Cardiol Rev, 2023)
Atrial fibrillation (AF) is the commonest arrhythmia in clinical practice and is associated with increased morbidity and mortality. Various predictive scores for new-onset AF have been proposed, but so far, none have been widely used in clinical practice. CHARGE-AF score was developed from a pooled diverse population from three large cohorts (Atherosclerosis Risk in Communities study, Cardiovascular Health Study and Framingham Heart Study). A simple 5-year predictive model includes the variables of age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction and heart failure. Recent studies report that the CHARGE-AF score has good discrimination for incident AF and seems to be a promising prediction model for this arrhythmia. New screening tools (smartphone apps, smartwatches) are rapidly developing for AF detection. Therefore, the wide application of the CHARGE-AF score in clinical practice and the upcoming usage of mobile health technologies and smartwatches may result in better AF prediction and adequate stroke prevention, especially in high-risk patients.
Keywords: Atherosclerosis; Atrial Fibrillation; Heart Failure; Humans; Incidence; Myocardial Infarction; Risk Assessment; Risk Factors

Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study. - Olson, Nels C; Doyle, Margaret F; Bůzková, Petra; Huber, Sally A; de Boer, Ian H; Sitlani, Colleen M; Tracy, Russell P; Psaty, Bruce M; Mukamal, Kenneth J; Delaney, Joseph A (Endocrinol Diabetes Metab, 2023)
INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain. METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA ), memory (CD45RO ), senescent (CD28 ), and T effector memory RA (TEMRA) (CD28 CD57 CD45RA ) CD4 and CD8 T cells, and memory B cells (CD19 CD27 ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 and CD8 subsets with incident DM risk. RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 , CD8 or CD19 cell phenotypes with incident DM. CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.
Keywords: CD28 Antigens; CD8-Positive T-Lymphocytes; Cellular Senescence; Diabetes Mellitus; Leukocytes, Mononuclear; Lymphocyte Subsets

Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders. - Kizer, Jorge R; Patel, Sheena; Ganz, Peter; Newman, Anne B; Bhasin, Shalender; Lee, Se-Jin; Cawthon, Peggy M; LeBrasseur, Nathan; Shah, Sanjiv J; Psaty, Bruce M; Tracy, Russell P; Cummings, Steven R (J Gerontol A Biol Sci Med Sci, 2023)
BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults. RESULTS: In 2,599 participants (age 75.2±4.3) followed for 10.8±5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function. CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.

Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults. - de Oliveira Otto, Marcia C; Wu, Jason H Y; Thacker, Evan L; Lai, Heidi Tsz Mung; Lemaitre, Rozenn N; Padhye, Nikhil; Song, Xiaoling; King, Irena B; Lopez, Oscar; Siscovick, David S; Mozaffarian, Dariush (J Alzheimers Dis, 2023)
BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study. METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

Clonal hematopoiesis is associated with protection from Alzheimer's disease. - Bouzid, Hind; Belk, Julia A; Jan, Max; Qi, Yanyan; Sarnowski, Chloe; Wirth, Sara; Ma, Lisa; Chrostek, Matthew R; Ahmad, Herra; Nachun, Daniel; Yao, Winnie; Beiser, Alexa; et al. (Nat Med, 2023)
Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk. - Tobias, Deirdre K; Manning, Alisa K; Wessel, Jennifer; Raghavan, Sridharan; Westerman, Kenneth E; Bick, Alexander G; DiCorpo, Daniel; Whitsel, Eric A; Collins, Jason; Correa, Adolfo; Cupples, L Adrienne; Dupuis, Josée; et al. (Diabetes Care, 2023)
OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. - Vlasschaert, Caitlyn; Robinson-Cohen, Cassianne; Kestenbaum, Bryan; Silver, Samuel A; Chen, Jian-Chun; Akwo, Elvis; Bhatraju, Pavan K; Zhang, Ming-Zhi; Cao, Shirong; Jiang, Ming; Wang, Yinqiu; Niu, Aolei; et al. (medRxiv, 2023)
Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. - Huque, Md Hamidul; Kootar, Scherazad; Eramudugolla, Ranmalee; Han, S Duke; Carlson, Michelle C; Lopez, Oscar L; Bennett, David A; Peters, Ruth; Anstey, Kaarin J (JAMA Netw Open, 2023)
IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited. OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI). DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023. MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk. RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar. CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Australia; Cohort Studies; Female; Heart Disease Risk Factors; Humans; Male; Risk Factors

Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. - Sargurupremraj, Muralidharan; Soumaré, Aïcha; Bis, Joshua C; Surakka, Ida; Jürgenson, Tuuli; Joly, Pierre; Knol, Maria J; Wang, Ruiqi; Yang, Qiong; Satizabal, Claudia L; Gudjonsson, Alexander; Mishra, Aniket; et al. (medRxiv, 2023)
IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population. KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

The determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study. - Bene-Alhasan, Yakubu; Siscovick, David S; Ix, Joachim H; Kizer, Jorge R; Tracy, Russell; Djoussé, Luc; Mukamal, Kenneth J (Metabol Open, 2023)
AIM: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults. METHODS: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n = 1924). RESULTS: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels. CONCLUSION: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

Determinants of mosaic chromosomal alteration fitness. - Pershad, Yash; Mack, Taralynn; Poisner, Hannah; Jakubek, Yasminka A; Stilp, Adrienne M; Mitchell, Braxton D; Lewis, Joshua P; Boerwinkle, Eric; Loos, Ruth J; Chami, Nathalie; Wang, Zhe; Barnes, Kathleen; et al. (medRxiv, 2023)
Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

{Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease? - Mantyh, W. G.; Cochran, J. N.; Taylor, J. W.; Broce, I. J.; Geier, E. G.; Bonham, L. W.; Anderson, A. G.; Sirkis, D. W.; Joie, R.; Iaccarino, L.; Chaudhary, K.; Edwards, L.; et al. (Alzheimers Dement (Amst), 2023)
There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort. - Mohebi, Reza; Wang, Dongyu; Lau, Emily S; Parekh, Juhi K; Allen, Norrina; Psaty, Bruce M; Benjamin, Emelia J; Levy, Daniel; Wang, Thomas J; Shah, Sanjiv J; Gottdiener, John S; Januzzi, James L; et al. (J Am Coll Cardiol, 2023)
BACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages. OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions. METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage. RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001). CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.
Keywords: American Heart Association; Atherosclerosis; Cardiology; Female; Heart Failure; Humans; Longitudinal Studies; Prognosis; United States

Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS. - Niezen, Sebastian; Connelly, Margery A; Hirsch, Calvin; Kizer, Jorge R; Benitez, Maria E; Minchenberg, Scott; Perez-Matos, Maria Camila; Jiang, Zhenghui Gordon; Mukamal, Kenneth J (J Am Heart Assoc, 2023)
Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
Keywords: Aged; Aging; Cardiovascular Diseases; Heart Failure; Humans; Incidence; Ketone Bodies

Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. - Kurniansyah, Nuzulul; Goodman, Matthew O; Khan, Alyna T; Wang, Jiongming; Feofanova, Elena; Bis, Joshua C; Wiggins, Kerri L; Huffman, Jennifer E; Kelly, Tanika; Elfassy, Tali; Guo, Xiuqing; Palmas, Walter; et al. (Nat Commun, 2023)
We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.
Keywords: Blood Pressure; Ethnicity; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Population Health; Risk Factors

Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition. - Newman, Anne B; Patel, Sheena; Kizer, Jorge; Lee, Se-Jin; Bhasin, Shalinder; Cawthon, Peggy; LeBrasseur, Nathan; Tracy, Russel P; Ganz, Peter; Cummings, Steve (J Gerontol A Biol Sci Med Sci, 2023)
BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. METHODS: We assessed Growth Differentiation Factor (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in in the Cardiovascular Health Study (N=1506) and the Health ABC study (N=1237). CLL-11 and Beta 2 microglobulin (B2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only) and incident dementia using correlations, linear regression and Cox proportional hazards models. RESULTS: In CHS, levels of GDF-11, GDF-8 and follistatin were not correlated cross sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities and atrophy on MRI as well as with incident dementia with an adjusted HR of 1.72 (95% CI=1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95%CI 1.07, 2.10) per doubling of GDF-8. CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicates TGF-B superfamily inhibition in the pathogenesis of dementia.

Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events. - Lidgard, Benjamin; Bansal, Nisha; Zelnick, Leila R; Hoofnagle, Andrew N; Fretts, Amanda M; Longstreth, William T; Shlipak, Michael G; Siscovick, David S; Umans, Jason G; Lemaitre, Rozenn N (EBioMedicine, 2023)
BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. FINDINGS: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke. INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses. - Marriott, Ross J; Murray, Kevin; Adams, Robert J; Antonio, Leen; Ballantyne, Christie M; Bauer, Douglas C; Bhasin, Shalender; Biggs, Mary L; Cawthon, Peggy M; Couper, David J; Dobs, Adrian S; Flicker, Leon; et al. (Ann Intern Med, 2023)
BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies;  = 21 074) and aggregate data (2 studies;  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. - de Las Fuentes, Lisa; Schwander, Karen L; Brown, Michael R; Bentley, Amy R; Winkler, Thomas W; Sung, Yun Ju; Munroe, Patricia B; Miller, Clint L; Aschard, Hugo; Aslibekyan, Stella; Bartz, Traci M; Bielak, Lawrence F; et al. (Front Genet, 2023)
Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. - Young, William J; Haessler, Jeffrey; Benjamins, Jan-Walter; Repetto, Linda; Yao, Jie; Isaacs, Aaron; Harper, Andrew R; Ramirez, Julia; Garnier, Sophie; Van Duijvenboden, Stefan; Baldassari, Antoine R; Concas, Maria Pina; et al. (Nat Commun, 2023)
The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
Keywords: Arrhythmias, Cardiac; Atrioventricular Block; Biomarkers; Cardiovascular Diseases; Electrocardiography; Genome-Wide Association Study; Humans; Risk Factors

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. - Einson, Jonah; Glinos, Dafni; Boerwinkle, Eric; Castaldi, Peter; Darbar, Dawood; de Andrade, Mariza; Ellinor, Patrick; Fornage, Myriam; Gabriel, Stacey; Germer, Soren; Gibbs, Richard; Hersh, Craig P; et al. (bioRxiv, 2023)
Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. - Weinstock, Joshua S; Laurie, Cecelia A; Broome, Jai G; Taylor, Kent D; Guo, Xiuqing; Shuldiner, Alan R; O'Connell, Jeffrey R; Lewis, Joshua P; Boerwinkle, Eric; Barnes, Kathleen C; Chami, Nathalie; Kenny, Eimear E; et al. (Sci Adv, 2023)
Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
Keywords: Germ-Line Mutation; Hematopoiesis; Humans; Middle Aged; Mutation; Mutation, Missense; Phenotype

Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts. - Yang, Chaojie; Veenstra, Jenna; Bartz, Traci; Pahl, Matthew; Hallmark, Brian; Chen, Yii-Der Ida; Westra, Jason; Steffen, Lyn; Brown, Christopher; Siscovick, David; Tsai, Michael; Wood, Alexis; et al. (Res Sq, 2023)
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of  < 5 x 10 , we confirmed association of the signal and found evidence of two additional signals (in and ) within 200 kb of the originally reported signal. Outside of the region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including , , and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure. - Guirette, Melanie; Lan, Jessie; McKeown, Nicola; Brown, Michael R; Chen, Han; de Vries, Paul S; Kim, Hyunju; Rebholz, Casey M; Morrison, Alanna C; Bartz, Traci M; Fretts, Amanda M; Guo, Xiuqing; et al. (medRxiv, 2023)
OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1. CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

High-risk carotid plaques and incident ischemic stroke in patients with atrial fibrillation in the Cardiovascular Health Study. - Noubiap, Jean Jacques; Thomas, Gijo; Kamtchum-Tatuene, Joseph; Middeldorp, Melissa E; Sanders, Prashanthan (Eur J Neurol, 2023)
BACKGROUND AND PURPOSE: Whether carotid artery disease could improve stroke risk stratification tools in patients with atrial fibrillation (AF) remains uncertain. This study was undertaken to investigate the risk of ischemic stroke associated with occlusive and nonocclusive carotid atherosclerotic disease in patients with AF in the prospective population-based Cardiovascular Health Study. METHODS: We included participants aged ≥65 years with AF. We used multivariable Cox regression analysis to explore the risk of ischemic stroke associated with the percentage of carotid stenosis, plaque irregularity, echogenicity, and vulnerability (markedly irregular, ulcerated, or hypoechoic plaques). RESULTS: A total of 1398 participants were included (55.2% female, 61.7% aged 65-74 years). The maximum carotid stenosis was <50%, 50%-99%, and 100% in 94.5%, 5%, and 0.5% of participants, respectively. High-risk plaques based on echogenicity and plaque irregularity were found in 25.6% and 8.9% of participants, respectively. After a median follow-up of 10.9 years (interquartile range = 7.5-15.6), 298 ischemic strokes were recorded. There was no difference in the incidence of ischemic stroke according to the degree of carotid artery stenosis (p = 0.44), plaque echogenicity (low vs. high risk, p = 0.68), plaque irregularity (low vs. high risk, p = 0.55), and plaque vulnerability (p = 0.86). The CHA₂DS₂-VASc score was associated with an increased risk of ischemic stroke (adjusted hazard ratio = 1.28, 95% confidence interval = 1.18-1.40, p < 0.001). Both maximum grade of stenosis and plaque vulnerability were not associated with incident ischemic stroke (all p > 0.05). CONCLUSIONS: Neither the degree of carotid stenosis nor the presence of vulnerable plaques was associated with incident ischemic stroke in this cohort of individuals with AF. This suggests that carotid disease was probably not a significant contributor to ischemic stroke in this population.
Keywords: Atrial Fibrillation; Carotid Artery Diseases; Carotid Stenosis; Female; Humans; Ischemic Stroke; Male; Plaque, Atherosclerotic; Prospective Studies; Risk Factors; Stroke

Hospital-Acquired Infection at Time of Stroke and Cognitive Decline: The Cardiovascular Health Study. - Cole, Kyril L; Boehme, Amelia K; Thacker, Evan L; Longstreth, W T; Brown, Bruce L; Gale, Shawn D; Hedges, Dawson W; Anderson, Jacqueline K; Elkind, Mitchell S V (Cerebrovasc Dis, 2023)
Introduction Hospital-acquired infections (HAIs) after stroke are associated with additional morbidity and mortality, but whether HAIs increase long-term cognitive decline in stroke patients is unknown. We hypothesized that older adults with incident stroke with HAI experience faster cognitive decline than those having stroke without HAI and those without stroke. Methods We performed a longitudinal analysis in the population-based prospective Cardiovascular Health Study. Medicare-eligible participants aged >65 years with and without incident stroke had cognition assessed annually. HAIs were assessed by hospital discharge codes. Global cognitive function was assessed annually by Modified Mini-Mental State Examination (3MSE) and executive function by Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate the mean decline and 95% confidence intervals (95% CI) for 3MSE and DSST scores by incident stroke and HAI status, adjusted for demographics and vascular risk factors. Results Among 5,443 participants >65 years without previous history of stroke, 393 participants had stroke with HAI (SI), 766 had a stroke only (SO), and 4,284 had no stroke (NS) throughout a maximum 9-year follow-up. For 3MSE, compared with NS participants, SO participants had a similar adjusted mean decline (additional 0.08 points/year, 95%CI -0.15, 0.31), while SI participants had a more rapid decline (additional 0.28 points/year, 95%CI 0.16, 0.40). Adjusted mean decline was 0.20 points/year faster (95%CI -0.05, 0.45) among SI than SO participants. For DSST, compared with NS participants, SO participants had a faster adjusted mean decline (additional 0.17 points/year (95%CI 0.003, 0.33), as did SI participants (additional 0.27 points/year (95%CI 0.19, 0.35). Conclusion Stroke, when accompanied by HAI, leads to a faster long-term decline in cognitive ability than in those without stroke. The clinical and public health implications of the effect of infection on post-stroke cognitive decline warrant further attention.

{Identification of circulating proteins associated with general cognitive function among middle-aged and older adults - Tin, A.; Fohner, A. E.; Yang, Q.; Brody, J. A.; Davies, G.; Yao, J.; Liu, D.; Caro, I.; Lindbohm, J. V.; Duggan, M. R.; Meirelles, O.; Harris, S. E.; et al. (Commun Biol, 2023)
2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Inflammation and Incident Conduction Disease. - Frimodt-Møller, Emilie K; Gottdiener, John S; Soliman, Elsayed Z; Kizer, Jorge R; Vittinghoff, Eric; Psaty, Bruce M; Biering-Sørensen, Tor; Marcus, Gregory M (J Am Heart Assoc, 2023)
Keywords: Cardiac Conduction System Disease; Electrocardiography; Heart Block; Humans; Inflammation

Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease. - Fan, KangHsien; Francis, Lily; Aslam, M Muaaz; Bedison, Margret A; Lawrence, Elizabeth; Acharya, Vibha; Snitz, Beth E; Ganguli, Mary; DeKosky, Steven T; Lopez, Oscar L; Feingold, Eleanor; Kamboh, M Ilyas (Neurobiol Aging, 2023)
A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.
Keywords: Alleles; Alzheimer Disease; Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Genotype; Heterozygote

Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis. - Liu, Fangyu; Austin, Thomas R; Schrack, Jennifer A; Chen, Jingsha; Walston, Jeremy; Mathias, Rasika A; Grams, Morgan; Odden, Michelle C; Newman, Anne; Psaty, Bruce M; Ramonfaur, Diego; Shah, Amil M; et al. (Aging Cell, 2023)
Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p  = 1 × 10 , p  = 2 × 10 ), transgelin (TAGLN; p  = 2 × 10 , p  = 6 × 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p  = 5 × 10 , p  = 1 × 10 ) and with a lower level of growth hormone receptor (GHR, p  = 3 × 10 , p  = 2 × 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

Lifestyle habits associated with cardiac conduction disease. - Frimodt-Møller, Emilie K; Soliman, Elsayed Z; Kizer, Jorge R; Vittinghoff, Eric; Psaty, Bruce M; Biering-Sørensen, Tor; Gottdiener, John S; Marcus, Gregory M (Eur Heart J, 2023)
AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant. METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults ≥ 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 ± 6 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association. CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status. - Chwa, Won Jong; Lopez, Oscar L; Longstreth, W T; Dai, Weiying; Raji, Cyrus A (J Alzheimers Dis, 2023)
BACKGROUND: Aging and Alzheimer's disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. OBJECTIVE: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. METHODS: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. RESULTS: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. CONCLUSION: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology - Chemparathy, A.; Guen, Y. L.; Chen, S.; Lee, E. G.; Leong, L.; Gorzynski, J.; Xu, G.; Belloy, M.; Kasireddy, N.; Tauber, A. P.; Williams, K.; Stewart, I.; et al. (medRxiv, 2023)
4 or its protein product as a viable therapeutic option.

Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores. - Hrytsenko, Yana; Shea, Benjamin; Elgart, Michael; Kurniansyah, Nuzulul; Lyons, Genevieve; Morrison, Alanna C; Carson, April P; Haring, Bernhard; Mitchel, Braxton D; Psaty, Bruce M; Jaeger, Byron C; Gu, C Charles; et al. (medRxiv, 2023)
We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.

Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease. - Robbins, John A; Bůzková, Petra; Barzilay, Joshua I; Cauley, Jane A; Fink, Howard A; Carbone, Laura D; Chen, Zhao; Stein, Phyllis K; Elam, Rachel; Sheets, Kerry; Mukamal, Kenneth J (Am J Med, 2023)
BACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified. METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture). RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years. CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.

Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. - Jakubek, Yasminka A; Zhou, Ying; Stilp, Adrienne; Bacon, Jason; Wong, Justin W; Ozcan, Zuhal; Arnett, Donna; Barnes, Kathleen; Bis, Joshua C; Boerwinkle, Eric; Brody, Jennifer A; Carson, April P; et al. (Nat Genet, 2023)
Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
Keywords: Black People; Genome, Human; Genome-Wide Association Study; Hispanic or Latino; Humans; Mosaicism; Precision Medicine

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. - Kavousi, Maryam; Bos, Maxime M; Barnes, Hanna J; Lino Cardenas, Christian L; Wong, Doris; Lu, Haojie; Hodonsky, Chani J; Landsmeer, Lennart P L; Turner, Adam W; Kho, Minjung; Hasbani, Natalie R; de Vries, Paul S; et al. (Nat Genet, 2023)
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. - Suzuki, Ken; Hatzikotoulas, Konstantinos; Southam, Lorraine; Taylor, Henry J; Yin, Xianyong; Lorenz, Kim M; Mandla, Ravi; Huerta-Chagoya, Alicia; Rayner, Nigel W; Bocher, Ozvan; Ana Luiza de, S V Arruda; Sonehara, Kyuto; et al. (medRxiv, 2023)
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. - Chen, Fang; Wang, Xingyan; Jang, Seon-Kyeong; Quach, Bryan C; Weissenkampen, J Dylan; Khunsriraksakul, Chachrit; Yang, Lina; Sauteraud, Renan; Albert, Christine M; Allred, Nicholette D D; Arnett, Donna K; Ashley-Koch, Allison E; et al. (Nat Genet, 2023)
Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
Keywords: Biology; Drug Repositioning; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Tobacco Use; Transcriptome

Multiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women. - Sarma, Amy A; Paniagua, Samantha M; Lau, Emily S; Wang, Dongyu; Liu, Elizabeth E; Larson, Martin G; Hamburg, Naomi M; Mitchell, Gary F; Kizer, Jorge; Psaty, Bruce M; Allen, Norrina B; Lely, A Titia; et al. (J Card Fail, 2023)
INTRODUCTION: Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear. METHODS: We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke. RESULTS: Among n=3931 FHS participants (mean age 48 ± 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91, p=0.02). CONCLUSIONS: Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.

Neighborhood greenspace and cognition: The cardiovascular health study. - Godina, Sara L; Rosso, Andrea L; Hirsch, Jana A; Besser, Lilah M; Lovasi, Gina S; Donovan, Geoffrey H; Garg, Parveen K; Platt, Jonathan M; Fitzpatrick, Annette L; Lopez, Oscar L; Carlson, Michelle C; Michael, Yvonne L (Health Place, 2023)
OBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status. METHODS: In a sample of non-demented older adults (n = 2141, average age = 75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated. RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI = 0.50-0.99). DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.

Neighborhood greenspace and neighborhood income associated with white matter grade worsening: Cardiovascular Health Study. - Besser, Lilah M; Lovasi, Gina S; Zambrano, Joyce Jimenez; Camacho, Simone; Dhanekula, Devi; Michael, Yvonne L; Garg, Parveen; Hirsch, Jana A; Siscovick, David; Hurvitz, Philip M; Biggs, Mary L; Galvin, James E; et al. (Alzheimers Dement (Amst), 2023)
INTRODUCTION: We examined whether a combined measure of neighborhood greenspace and neighborhood median income was associated with white matter hyperintensity (WMH) and ventricle size changes. METHODS: The sample included 1260 cognitively normal ≥ 65-year-olds with two magnetic resonance images (MRI; ≈ 5 years apart). WMH and ventricular size were graded from 0 (least) to 9 (most) abnormal (worsening = increase of ≥1 grade from initial to follow-up MRI scans). The four-category neighborhood greenspace-income measure was based on median neighborhood greenspace and income values at initial MRI. Multivariable logistic regression tested associations between neighborhood greenspace-income and MRI measures (worsening vs. not). RESULTS: White matter grade worsening was more likely for those in lower greenspace-lower income neighborhoods than higher greenspace-higher income neighborhoods (odds ratio = 1.73; 95% confidence interval = 1.19-2.51). DISCUSSION: The combination of lower neighborhood income and lower greenspace may be a risk factor for worsening white matter grade on MRI. However, findings need to be replicated in more diverse cohorts. HIGHLIGHTS: Population-based cohort of older adults (≥ 65 years) with greenspace and MRI dataCombined measure of neighborhood greenspace and neighborhood income at initial MRIMRI outcomes included white matter hyperintensities (WMH) and ventricular sizeLongitudinal change in MRI outcomes measured approximately 5 years apartWorsening WMH over time more likely for lower greenspace-lower income neighborhoods.

Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study. - Ahiawodzi, Peter; Solaru, Khendi White; Chaves, Paulo H M; Ix, Joachim H; Kizer, Jorge R; Tracy, Russell P; Newman, Anne; Siscovick, David; Djoussé, Luc; Mukamal, Kenneth J (Atherosclerosis, 2023)
BACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons. METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI. RESULTS: Mean age was 74.8 years, 59% were female, and 17% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95%CI = 1.06-2.13, p = 0.02) across extreme tertiles, and 1.14 (95%CI = 0.99-1.31, p = 0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95%CI = 0.69-1.32, p = 0.76) across extreme tertiles, and 1.03 (95%CI = 0.89-1.20, p = 0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up. CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.

Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. - Bockus, Lee B; Jensen, Paul N; Fretts, Amanda M; Hoofnagle, Andrew N; McKnight, Barbara; Sitlani, Colleen M; Siscovick, David S; King, Irena B; Psaty, Bruce M; Sotoodehnia, Nona; Lemaitre, Rozenn N (JAMA Netw Open, 2023)
IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known. OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023. EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons. MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk. RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]). CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.
Keywords: Aged; Ceramides; Cohort Studies; Death, Sudden, Cardiac; Eicosanoic Acids; Fatty Acids; Female; Humans; Male; Sphingolipids; Sphingomyelins

Plasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine. - Carbone, Laura; Bůzková, Petra; Fink, Howard A; Robbins, John A; Barzilay, Joshua I; Elam, Rachel E; Isales, Carlos; Connelly, Margery A; Mukamal, Kenneth J (J Clin Endocrinol Metab, 2023)
OBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS). DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS. SETTING: Community. PARTICIPANTS: 1850 men (38% of cohort) and women; mean age 73. MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine. RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07). CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study. - Kalani, Rizwan; Bartz, Traci M; Psaty, Bruce M; Elkind, Mitchell S V; Floyd, James S; Gerszten, Robert E; Shojaie, Ali; Heckbert, Susan R; Bis, Joshua C; Austin, Thomas R; Tirschwell, David L; Delaney, Joseph A C; et al. (Neurology, 2023)
BACKGROUND: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS). METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation. RESULTS: Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction. CONCLUSIONS: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study. - Gharib, Arya R; Jensen, Paul N; Psaty, Bruce M; Hoofnagle, Andrew N; Siscovick, David; Gharib, Sina A; Sitlani, Colleen M; Sotoodehnia, Nona; Lemaitre, Rozenn N (ERJ Open Res, 2023)
RATIONALE: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function. METHODS: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV) and odds of COPD, respectively. RESULTS: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD. CONCLUSION: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV within individuals or with incident COPD.

Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis. - Lemaitre, Rozenn N; Jensen, Paul N; Wang, Zeneng; Fretts, Amanda M; Sitlani, Colleen M; Nemet, Ina; Sotoodehnia, Nona; de Oliveira Otto, Marcia C; Zhu, Weifei; Budoff, Matt; Longstreth, W T; Psaty, Bruce M; et al. (J Am Heart Assoc, 2023)
Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60% (CHS) and 53% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.
Keywords: Aged; Atherosclerosis; Female; Humans; Ischemic Stroke; Methylamines; Oxides; Prospective Studies; Risk Factors; Stroke; United States

{Polygenic burden of short tandem repeat expansions promote risk for Alzheimer's disease - Guo, M. H.; Lee, W. P.; Vardarajan, B.; Schellenberg, G. D.; Phillips-Cremins, J. (medRxiv, 2023)
30 STR expansions had 3.62-fold higher odds of having AD and had more severe AD neuropathology. AD STR expansions were highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome promote risk of AD.

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer. - Lastwika, Kristin J; Kunihiro, Andrew; Solan, Joell L; Zhang, Yuzheng; Taverne, Lydia R; Shelley, David; Rho, Jung-Hyun; Randolph, Timothy W; Li, Christopher I; Grogan, Eric L; Massion, Pierre P; Fitzpatrick, Annette L; et al. (Sci Transl Med, 2023)
Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.
Keywords: Autoantibodies; Humans; Lung Neoplasms; Protein Processing, Post-Translational; Small Cell Lung Carcinoma

Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. - Li, Xihao; Quick, Corbin; Zhou, Hufeng; Gaynor, Sheila M; Liu, Yaowu; Chen, Han; Selvaraj, Margaret Sunitha; Sun, Ryan; Dey, Rounak; Arnett, Donna K; Bielak, Lawrence F; Bis, Joshua C; et al. (Nat Genet, 2023)
Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.
Keywords: Exome Sequencing; Genome-Wide Association Study; Lipids; Phenotype; Whole Genome Sequencing

Prediction of Multiple Individual Primary Cardiovascular Events Using Pooled Cohorts. - Sussman, Jeremy B; Whitney, Rachael T; Burke, James F; Hayward, Rodney A; Galecki, Andrzej; Sidney, Stephen; Allen, Norrina Bai; Gottesman, Rebecca F; Heckbert, Susan R; Longstreth, William T; Psaty, Bruce M; Elkind, Mitchell S V; et al. (medRxiv, 2023)
INTRODUCTION: Most current clinical risk prediction scores for cardiovascular disease prevention use a composite outcome. Risk prediction scores for specific cardiovascular events could identify people who are at higher risk for some events than others informing personalized care and trial recruitment. We sought to predict risk for multiple different events, describe how those risks differ, and examine if these differences could improve treatment priorities. METHODS: We used participant-level data from five cohort studies. We included participants between 40 and 79 years old who had no history of myocardial infarction (MI), stroke, or heart failure (HF). We made separate models to predict 10-year rates of first atherosclerotic cardiovascular disease (ASCVD), first fatal or nonfatal MI, first fatal or nonfatal stroke, new-onset HF, fatal ASCVD, fatal MI, fatal stroke, and all-cause mortality using established ASCVD risk factors. To limit overfitting, we used elastic net regularization with alpha = 0.75. We assessed the models for calibration, discrimination, and for correlations between predicted risks for different events. We also estimated the potential impact of varying treatment based on patients who are high risk for some ASCVD events, but not others. RESULTS: Our study included 24,505 people; 55.6% were women, and 20.7% were non-Hispanic Black. Our models had C-statistics between 0.75 for MI and 0.85 for HF, good calibration, and minimal overfitting. The models were least similar for fatal stroke and all MI (0.58). In 1,840 participants whose risk of MI but not stroke or all-cause mortality was in the top quartile, we estimate one blood pressure-lowering medication would have a 2.4% chance of preventing any ASCVD event per 10 years. A moderate-strength statin would have a 2.1% chance. In 1,039 participants who had top quartile risk of stroke but not MI or mortality, a blood pressure-lowering medication would have a 2.5% chance of preventing an event, but a moderate-strength statin, 1.6%. CONCLUSION: We developed risk scores for eight key clinical events and found that cardiovascular risk varies somewhat for different clinical events. Future work could determine if tailoring decisions by risk of separate events can improve care.

Prospective Longitudinal Perfusion in Probable Alzheimer's Disease Correlated with Atrophy in Temporal Lobe. - Zhou, Tony D; Zhang, Zongpai; Balachandrasekaran, Arvind; Raji, Cyrus A; Becker, James T; Kuller, Lewis H; Ge, Yulin; Lopez, Oscar L; Dai, Weiying; Gach, H Michael (Aging Dis, 2023)
Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). - Jonmundsson, Thorarinn; Steindorsdottir, Anna E; Austin, Thomas R; Frick, Elisabet A; Axelsson, Gisli T; Launer, Lenore; Psaty, Bruce M; Loureiro, Joseph; Orth, Anthony P; Aspelund, Thor; Emilsson, Valur; Floyd, James S; et al. (Europace, 2023)
AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points. CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.
Keywords: Atrial Fibrillation; Biomarkers; Endosomal Sorting Complexes Required for Transport; Humans; Natriuretic Peptide, Brain; Oxidoreductases Acting on Sulfur Group Donors; Peptide Fragments; Prognosis; Prospective Studies; Proteomics; Risk Factors

Proteomic prediction of incident heart failure and its main subtypes. - Emilsson, Valur; Jonsson, Brynjolfur G; Austin, Thomas R; Gudmundsdottir, Valborg; Axelsson, Gisli T; Frick, Elisabet A; Jonmundsson, Thorarinn; Steindorsdottir, Anna E; Loureiro, Joseph; Brody, Jennifer A; Aspelund, Thor; Launer, Lenore J; et al. (Eur J Heart Fail, 2023)
AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables. METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS). CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.

Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. - Wang, Yuxuan; Selvaraj, Margaret Sunitha; Li, Xihao; Li, Zilin; Holdcraft, Jacob A; Arnett, Donna K; Bis, Joshua C; Blangero, John; Boerwinkle, Eric; Bowden, Donald W; Cade, Brian E; Carlson, Jenna C; et al. (medRxiv, 2023)
Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

{Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study - é, H. T.; Liu, X.; Odden, M. C.; Moseholm, K. F.; Seshadri, S.; Satizabal, C. L.; Lopez, O. L.; Bis, J. C.; é, L.; Fohner, A. E.; Psaty, B. M.; Tracy, R. P.; et al. (Alzheimers Dement, 2023)
Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated.\ We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline.\ 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline.\ Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. - Pase, Matthew P; Harrison, Stephanie; Misialek, Jeffrey R; Kline, Christopher E; Cavuoto, Marina; Baril, Andree-Ann; Yiallourou, Stephanie; Bisson, Alycia; Himali, Dibya; Leng, Yue; Yang, Qiong; Seshadri, Sudha; et al. (JAMA Netw Open, 2023)
IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes. OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023. EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG. MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance. RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition. CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

Social networks, social support, and life expectancy in older adults: the Cardiovascular Health Study. - Bhatia, Roma; Hirsch, Calvin; Arnold, Alice M; Newman, Anne B; Mukamal, Kenneth J (Arch Gerontol Geriatr, 2023)
BACKGROUND: Social support and social networks have long been postulated to impact health outcomes but their impact on life expectancy and disability in older adults remains poorly quantified. METHODS: As part of the Cardiovascular Health Study, we followed 5,749 adults aged 65 years and older from 4 US field centers for 25 years. We assessed the Lubben social network score [range 0-50] and a social support score [range 0-24] derived from the Interpersonal Support Evaluation List (ISEL-12) in two consecutive years starting at study recruitment. We used remaining years of life (YOL) from study enrollment to death to approximate life expectancy. We defined years of active life (YAL) as the number of study years in which participants lived without any difficulties in activities of daily living. We used compression of disability to reflect the proportion of life lived able (YAL/YOL). We used linear regression to adjust for socio-demographics and comorbidity. RESULTS: The mean (standard deviation [SD]) scores were 32.3 ± 6.8 points for social network score and 8.3 ± 2.4 points for social support score. For every 1-SD increase in social network score, adjusted participant life expectancy was 0.40 years higher (95% CI 0.22-0.58; p<0.0001) and disability-free life expectancy 0.35 years higher (95% CI 0.18-0.53; p<0.0001). The association with life expectancy was modified by participant age (p<0.001), but it remained significant even among participants aged ≥75 years (3 months per SD; 95% CI 0.1-6 months, p = 0.04). Further adjustment for frailty did not attenuate the estimates. The social support scale was not significantly associated with YOL or YAL after adjustment for social network score, and neither measure was associated with compression of disability. DISCUSSION: In older adults, higher social network scores are significantly associated with longer life expectancy and disability-free life expectancy.

A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. - Li, Xihao; Chen, Han; Selvaraj, Margaret Sunitha; Van Buren, Eric; Zhou, Hufeng; Wang, Yuxuan; Sun, Ryan; McCaw, Zachary R; Yu, Zhi; Arnett, Donna K; Bis, Joshua C; Blangero, John; et al. (bioRxiv, 2023)
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

{Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects - Wang, H.; Dombroski, B. A.; Cheng, P. L.; Tucci, A.; Si, Y. Q.; Farrell, J. J.; Tzeng, J. Y.; Leung, Y. Y.; Malamon, J. S.; Wang, L. S.; Vardarajan, B. N.; Farrer, L. A.; et al. (medRxiv, 2023)
. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.\ Alzheimer's disease, Structural variation, Copy number variation.

{Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects - Lee, W. P.; Wang, H.; Dombroski, B.; Cheng, P. L.; Tucci, A.; Si, Y. Q.; Farrell, J.; Tzeng, J. Y.; Leung, Y. Y.; Malamon, J.; Wang, L. S.; Vardarajan, B.; et al. (Res Sq, 2023)
. We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics.

Substitution of self-reported measures for objectively assessed grip strength and slow walk in the Physical Frailty Phenotype: ramifications for validity. - Bandeen-Roche, Karen; Tian, Jing; Buta, Brian; Walston, Jeremy; Xue, Qian-Li (BMC Geriatr, 2023)
BACKGROUND: Frailty assessment promises to identify older adults at risk for adverse consequences following stressors and target interventions to improve health outcomes. The Physical Frailty Phenotype (PFP) is a widely-studied, well validated assessment but incorporates performance-based slow walk and grip strength criteria that challenge its use in some clinical settings. Variants replacing performance-based elements with self-reported proxies have been proposed. Our study evaluated whether commonly available disability self-reports could be substituted for the performance-based criteria in the PFP while still identifying as "frail" the same subpopulations of individuals. METHODS: Parallel analyses were conducted in 3393 female and 2495 male Cardiovascular Health Study, Round 2 participants assessed in 1989-90. Candidate self-reported proxies for the phenotype's "slowness" and "weakness" criteria were evaluated for comparable prevalence and agreement by mode of measurement. For best-performing candidates: Frailty status (3 + positive criteria out of 5) was compared for prevalence and agreement between the PFP and mostly self-reported versions. Personal characteristics were compared between those adjudicated as frail by (a) only a self-reported version; (b) only the PFP; (c) both, using bivariable analyses and multinomial logistic regression. RESULTS: Self-reported difficulty walking ½ mile was selected as a proxy for the phenotype's slowness criterion. Two self-reported weakness proxies were examined: difficulty transferring from a bed or chair or gripping with hands, and difficulty as just defined or in lifting a 10-pound bag. Prevalences matched to within 4% between self-reported and performance-based criteria in the whole sample, but in all cases the self-reported prevalence for women exceeded that for men by 11% or more. Cross-modal agreement was moderate, with by-criterion and frailty-wide Kappa statistics of 0.55-0.60 in all cases. Frail subgroups (a), (b), (c) were independently discriminated (p < 0.05) by race, BMI, and depression in women; by age in men; and by self-reported health for both. CONCLUSIONS: Commonly used self-reported disability items cannot be assumed to stand in for performance-based criteria in the PFP. We found subpopulations identified as frail by resultant phenotypes versus the original phenotype to systematically differ. Work to develop self-reported proxies that more closely replicate their objective phenotypic counterparts than standard disability self-reports is needed.
Keywords: Advance Directives; Female; Frailty; Hand Strength; Humans; Male; Phenotype; Self Report

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. - Kwak, Soo Heon; Hernandez-Cancela, Ryan B; DiCorpo, Daniel A; Condon, David E; Merino, Jordi; Wu, Peitao; Brody, Jennifer A; Yao, Jie; Guo, Xiuqing; Ahmadizar, Fariba; Meyer, Mariah; Sincan, Murat; et al. (medRxiv, 2023)
BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D. CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

Time-Varying Food Retail and Incident Disease in the Cardiovascular Health Study. - Lovasi, Gina S; Boise, Sarah; Jogi, Siddharth; Hurvitz, Philip M; Rundle, Andrew G; Diez, Julia; Hirsch, Jana A; Fitzpatrick, Annette; Biggs, Mary L; Siscovick, David S (Am J Prev Med, 2023)
INTRODUCTION: Natural experiments can strengthen evidence linking neighborhood food retail presence to dietary intake patterns and cardiometabolic health outcomes, yet sample size and follow-up duration are typically not extensive. To complement natural experiment evidence, longitudinal data were used to estimate the impacts of neighborhood food retail presence on incident disease. METHODS: The Cardiovascular Health Study recruited adults aged 65+ years in 1989-1993. Analyses conducted in 2021-2022 included those in good baseline health, with addresses updated annually through the year of death (restricted to 91% who died during >2 decades of cohort follow-up). Baseline and annually updated presence of 2 combined food retail categories (supermarkets/produce markets and convenience/snack focused) was characterized using establishment-level data for 1-km and 5-km Euclidean buffers. Cox proportional hazards models estimated associations with time to each incident outcome (cardiovascular disease, diabetes), adjusting for individual and area-based confounders. RESULTS: Among 2,939 participants, 36% with baseline supermarket/produce market presence within 1 km had excess incident cardiovascular disease (hazard ratio=1.12; 95% CI=1.01, 1.24); the association was attenuated and no longer statistically significant after adjustment for sociodemographic characteristics. Adjusted associations were robustly null for time-varying supermarket/produce market or convenience/fast food retail presence across analyses with outcomes of cardiovascular disease or diabetes incidence. CONCLUSIONS: Food environment changes continue to be studied to provide an evidence base for policy decisions, and null findings in this longitudinal analysis add literature that casts doubt on the sufficiency of strategies targeting food retail presence alone of an elderly cohort for curtailing incident events of clinical importance.

Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults. - Massera, Daniele; Bartz, Traci M; Biggs, Mary L; Sotoodehnia, Nona; Reiner, Alexander P; Semba, Richard D; Gottdiener, John S; Psaty, Bruce M; Owens, David S; Kizer, Jorge R (Heart, 2023)
OBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics. METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures). RESULTS: Of 5390 participants (age 72.9±5.6 years, 57.6% female, 12.5% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A (LpPLA) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFR) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association. CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA activity, sCD14 and IL-6, and eGFR. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.

A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies. - Srinivasan, Shylaja; Wu, Peitao; Mercader, Josep M; Udler, Miriam S; Porneala, Bianca C; Bartz, Traci M; Floyd, James S; Sitlani, Colleen; Guo, Xiquing; Haessler, Jeffrey; Kooperberg, Charles; Liu, Jun; et al. (J Endocr Soc, 2023)
CONTEXT: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight. OBJECTIVE: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D. RESULTS: The T1D PS was not associated with T2D both in CHARGE ( = .15) and in the MGB Biobank ( = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, = .03) in CHARGE T2D cases but not with other outcomes. CONCLUSION: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. - Hasbani, Natalie R; Westerman, Kenneth E; Heon Kwak, Soo; Chen, Han; Li, Xihao; DiCorpo, Daniel; Wessel, Jennifer; Bis, Joshua C; Sarnowski, Chloe; Wu, Peitao; Bielak, Lawrence F; Guo, Xiuqing; et al. (Circ Genom Precis Med, 2023)
BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease. - Ukraintseva, Svetlana; Duan, Matt; Simanek, Amanda M; Holmes, Rachel; Bagley, Olivia; Rajendrakumar, Aravind L; Yashkin, Arseniy P; Akushevich, Igor; Tropsha, Alexander; Whitson, Heather; Yashin, Anatoliy; Arbeev, Konstantin (J Alzheimers Dis, 2023)
Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer's disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. - Kootar, S; Huque, M H; Eramudugolla, R; Rizzuto, D; Carlson, M C; Odden, M C; Lopez, O L; Qiu, C; Fratiglioni, L; Han, S D; Bennett, D A; Peters, R; et al. (J Prev Alzheimers Dis, 2023)
BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research. OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model. RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project. CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.
Keywords: Aging; Alzheimer Disease; Cohort Studies; Dementia; Humans; Independent Living

Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. - Huffman, Jennifer E; Nicolas, Jayna; Hahn, Julie; Heath, Adam S; Raffield, Laura M; Yanek, Lisa R; Brody, Jennifer A; Thibord, Florian; Almasy, Laura; Bartz, Traci M; Bielak, Lawrence F; Bowler, Russell P; et al. (medRxiv, 2023)
UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. - Seyerle, Amanda A; Laurie, Cecelia A; Coombes, Brandon J; Jain, Deepti; Conomos, Matthew P; Brody, Jennifer; Chen, Ming-Huei; Gogarten, Stephanie M; Beutel, Kathleen M; Gupta, Namrata; Heckbert, Susan R; Jackson, Rebecca D; et al. (Circ Genom Precis Med, 2023)
Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. - Armstrong, Nicole D; Srinivasasainagendra, Vinodh; Ammous, Farah; Assimes, Themistocles L; Beitelshees, Amber L; Brody, Jennifer; Cade, Brian E; Ida Chen, Yii-Der; Chen, Han; de Vries, Paul S; Floyd, James S; Franceschini, Nora; et al. (Front Genet, 2023)
Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. - Zhang, Xinruo; Brody, Jennifer A; Graff, Mariaelisa; Highland, Heather M; Chami, Nathalie; Xu, Hanfei; Wang, Zhe; Ferrier, Kendra; Chittoor, Geetha; Josyula, Navya S; Li, Xihao; Li, Zilin; et al. (medRxiv, 2023)
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. - Jiang, Min-Zhi; Gaynor, Sheila M; Li, Xihao; Van Buren, Eric; Stilp, Adrienne; Buth, Erin; Wang, Fei Fei; Manansala, Regina; Gogarten, Stephanie M; Li, Zilin; Polfus, Linda M; Salimi, Shabnam; et al. (bioRxiv, 2023)
Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations. - Feofanova, Elena V; Brown, Michael R; Alkis, Taryn; Manuel, Astrid M; Li, Xihao; Tahir, Usman A; Li, Zilin; Mendez, Kevin M; Kelly, Rachel S; Qi, Qibin; Chen, Han; Larson, Martin G; et al. (Nat Commun, 2023)
Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.
Keywords: Ethnicity; Genome-Wide Association Study; Humans; Metabolome; Polymorphism, Single Nucleotide; Quantitative Trait Loci

Association analysis of mitochondrial DNA heteroplasmic variants: methods and application. - Sun, Xianbang; Bulekova, Katia; Yang, Jian; Lai, Meng; Pitsillides, Achilleas N; Liu, Xue; Zhang, Yuankai; Guo, Xiuqing; Yong, Qian; Raffield, Laura M; Rotter, Jerome I; Rich, Stephen S; et al. (medRxiv, 2024)
We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

Association of thyroid dysfunction in individuals ≥ 65 years of age with subclinical cardiac abnormalities. - Barasch, Eddy; Gottdiener, John; Bůzková, Petra; Cappola, Anne; Shah, Sanjiv; DeFilippi, Christopher; Gardin, Julius; Kizer, Jorge R (J Clin Endocrinol Metab, 2024)
CONTEXT: The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined. OBJECTIVE: To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease. DESIGN: Cross-sectional analysis. SETTING: The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States. PATIENTS: Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation. INTERVENTIONS: Clinical evaluation, blood sampling and biomarker measurement, 2-dimensional and speckle-tracking echocardiography. MAIN OUTCOME MEASURE(S): Left heart myocardial deformation, circulating biomarkers of diastolic overload (NT-proBNP), fibrosis (sST2, gal-3), and cardiomyocyte injury (hs-cTnT). RESULTS: SCH was associated with higher NT-proBNP (beta = 0.17, p = 0.004), whereas OH was associated with higher hs-cTnT (beta = 0.29, p = 0.005). There were also suggestive associations of SCH with higher sST2, as well as endo-SCT with higher gal-3 and lower (worse) left atrial reservoir strain. Left ventricular longitudinal strain and end-diastolic strain rate did not differ significantly from euthyroid participants in SCH, OH, or exo-SCT. CONCLUSIONS: In this free-living elderly cohort, subclinical and overt hypothyroidism were associated with abnormalities of blood biomarkers consistent with diastolic overload and myocardial necrosis respectively, whereas subclinical hyperthyroidism tended to be associated with myocardial fibrosis and decreased left atrial strain. Our findings could represent stage B heart failure and illuminate distinct aspects of the pathobiology of heart disease related to thyroid gland dysfunction with potential clinical implications.

Associations of Neurological Biomarkers in Serum with Gait Measures: The Cardiovascular Health Study. - Nadkarni, Abhijay; Mukamal, Kenneth J; Zhu, Xiaonan; Siscovick, David; Brach, Jennifer S; Jacob, Mini; Seshadri, Sudha; Abe, Temidayo; Rosano, Caterina; Djoussé, Luc; Rosso, Andrea L (J Gerontol A Biol Sci Med Sci, 2024)
BACKGROUND: Gait impairment leads to increased mobility decline and may have neurological contributions. This study explores how neurological biomarkers are related to gait in older adults. METHODS: We studied participants in the Cardiovascular Health Study, a population-based cohort of older Americans, who underwent a serum biomarker assessment from samples collected in 1996-97 for neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau (n=1959, mean age=78.0 years, 60.8% female). In a subsample (n=380), cross-sectional associations with quantitative gait measures were explored. This subsample was assessed on a mat for gait speed, step length, double support time, step time, step length variability and step time variability. Gait speed was also measured over a 15-ft walkway annually from 1996-97 to 1998-99, for longitudinal analyses. Linear regression models assessed cross-sectional associations of biomarkers with gait measures, while mixed effects models assessed longitudinal gait speed change from baseline to 1998-99. RESULTS: NfL was significantly associated with annual gait speed decline (standardized β = -0.64 m/s, 95% CI: [-1.23, -0.06]) after adjustment for demographic and health factors. Among gait mat-assessed phenotypes, NfL was also cross-sectionally associated with gait speed (β = 0.001 m/s [0.0003, 0.002]) but not with other gait measures. None of the remaining biomarkers were significantly related to gait in either longitudinal or cross-sectional analyses. CONCLUSION: Higher NfL levels were related to greater annual gait speed decline. Gait speed decline may be related to axonal degeneration. The clinical utility of NfL should be explored.

A comparative study of structural variant calling in WGS from Alzheimer's disease families. - Malamon, John S; Farrell, John J; Xia, Li Charlie; Dombroski, Beth A; Das, Rueben G; Way, Jessica; Kuzma, Amanda B; Valladares, Otto; Leung, Yuk Yee; Scanlon, Allison J; Lopez, Irving Antonio Barrera; Brehony, Jack; et al. (Life Sci Alliance, 2024)
Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.
Keywords: Alzheimer Disease; Humans; Whole Genome Sequencing

Development and Validation of the American Heart Association's PREVENT Equations. - Khan, Sadiya S; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Grams, Morgan E; Surapaneni, Aditya; Blaha, Michael J; Carson, April P; Chang, Alexander R; Ciemins, Elizabeth; Go, Alan S; Gutierrez, Orlando M; et al. (Circulation, 2024)
BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; =0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.
Keywords: Adult; Aged; Albumins; American Heart Association; Atherosclerosis; Cardiovascular Diseases; Creatinine; Female; Glycated Hemoglobin; Heart Failure; Humans; Male; Middle Aged; Risk Assessment; Risk Factors

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol. - Zhang, Yiyi; Dron, Jacqueline S; Bellows, Brandon K; Khera, Amit V; Liu, Junxiu; Balte, Pallavi P; Oelsner, Elizabeth C; Amr, Sami Samir; Lebo, Matthew S; Nagy, Anna; Peloso, Gina M; Natarajan, Pradeep; et al. (JAMA Cardiol, 2024)
IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status. MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

{A genetic association study of circulating coagulation Factor VIII and von Willebrand Factor levels - de Vries, P. S.; Reventun, P.; Brown, M. R.; Heath, A. S.; Huffman, J. E.; Le, N. Q.; Bebo, A.; Brody, J. A.; Temprano-Sagrera, G.; Raffield, L. M.; Ozel, A. B.; Thibord, F.; et al. (Blood, 2024)
10-9) at seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and one for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

{Genetic associations with dementia-related proteinopathy: Application of item response theory - Katsumata, Y.; Fardo, D. W.; Shade, L. M. P.; Wu, X.; Karanth, S. D.; Hohman, T. J.; Schneider, J. A.; Bennett, D. A.; Farfel, J. M.; Gauthreaux, K.; Mock, C.; Kukull, W. A.; et al. (Alzheimers Dement, 2024)
Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.\ -synuclein, and TDP-43.\ -synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.\ A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.\ Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. - Suzuki, Ken; Hatzikotoulas, Konstantinos; Southam, Lorraine; Taylor, Henry J; Yin, Xianyong; Lorenz, Kim M; Mandla, Ravi; Huerta-Chagoya, Alicia; Melloni, Giorgio E M; Kanoni, Stavroula; Rayner, Nigel W; Bocher, Ozvan; et al. (Nature, 2024)
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

{Genome-wide association study of preserved ratio impaired spirometry (PRISm) - Higbee, D. H.; Lirio, A.; Hamilton, F.; Granell, R.; Wyss, A. B.; London, S. J.; Bartz, T. M.; Gharib, S. A.; Cho, M. H.; Wan, E.; Silverman, E.; Crapo, J. D.; et al. (Eur Respir J, 2024)
{0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.\ We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.\ =0.12

The Gut Microbial Metabolite Trimethylamine N-oxide, Incident CKD, and Kidney Function Decline. - Wang, Meng; Tang, W H Wilson; Li, Xinmin S; de Oliveira Otto, Marcia C; Lee, Yujin; Lemaitre, Rozenn N; Fretts, Amanda; Nemet, Ina; Sotoodehnia, Nona; Sitlani, Colleen M; Budoff, Matthew; DiDonato, Joseph A; et al. (J Am Soc Nephrol, 2024)
BACKGROUND: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline. METHODS: We included 10,564 participants from two community-based, prospective cohorts with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and Cystatin C were measured up to 4 times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥ 30% from baseline and a resulting eGFR<60 ml/min/1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels. RESULTS: During a median follow-up of 9.4 years (interquartile range: 9.1-11.6 years), 979 incident CKD events occurred. Higher TMAO levels associated with higher risk of incident CKD (2nd to 5th vs. 1st quintile HR[95%CI]= 1.65 [1.22-2.23], 1.68 [1.26-2.25], 2.28 [1.72-3.02], and 2.24[1.68-2.98], respectively) and greater annualized eGFR decline ( 2nd to 5th vs. 1st quintile annualized eGFR change= -0.21 [-0.32, -0.09], -0.17 [-0.29, -0.05], -0.35 [-0.47, -0.22], and -0.43[-0.56, -0.30], respectively) with monotonic dose-response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors including diabetes, per 10 mmHg of higher systolic blood pressure, per 10 years of older age, and Black race. CONCLUSIONS: In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.

Human whole-exome genotype data for Alzheimer's disease. - Leung, Yuk Yee; Naj, Adam C; Chou, Yi-Fan; Valladares, Otto; Schmidt, Michael; Hamilton-Nelson, Kara; Wheeler, Nicholas; Lin, Honghuang; Gangadharan, Prabhakaran; Qu, Liming; Clark, Kaylyn; Kuzma, Amanda B; et al. (Nat Commun, 2024)
The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.
Keywords: Alzheimer Disease; Computational Biology; Data Accuracy; Exome; Genotype; Humans

Iron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals. - Sharma, Shilpa; Katz, Ronit; Chaves, Paulo H M; Hoofnagle, Andrew N; Kizer, Jorge R; Bansal, Nisha; Ganz, Tomas; Ix, Joachim H (ESC Heart Fail, 2024)
AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function. METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N = 414 total HF cases]) aged ≥ 65 years without HF (41% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as "iron replete" (27.3%), "functional iron deficiency" (7.7%), "iron deficiency" (11.8%), "mixed iron deficiency" (5.6%), "high iron" (9.3%) and "non-classified" (38.1%), consistent with prior studies. RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2). CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures. - Austin, Thomas R; Fink, Howard A; Jalal, Diana I; Törnqvist, Anna E; Bůzková, Petra; Barzilay, Joshua I; Lu, Tianyuan; Carbone, Laura; Gabrielsen, Maiken E; Grahnemo, Louise; Hveem, Kristian; Jonasson, Christian; et al. (J Bone Miner Res, 2024)
Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations. - Nagarajan, Pavithra; Winkler, Thomas W; Bentley, Amy R; Miller, Clint L; Kraja, Aldi T; Schwander, Karen; Lee, Songmi; Wang, Wenyi; Brown, Michael R; Morrison, John L; Giri, Ayush; O'Connell, Jeffrey R; et al. (medRxiv, 2024)
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis. - Shelbaya, Khaled; Arthur, Victoria; Yang, Yimin; Dorbala, Pranav; Buckley, Leo; Claggett, Brian; Skali, Hicham; Dufresne, Line; Yang, Ta-Yu; Engert, James C; Thanassoulis, George; Floyd, James; et al. (J Am Coll Cardiol, 2024)
BACKGROUND: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES: The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.
Keywords: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Biomarkers; Calcinosis; Humans; Matrix Metalloproteinase 12; Middle Aged; Proteomics; Risk Factors

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study. - Harrington, Laura B; Ehlert, Alexa N; Thacker, Evan L; Jenny, Nancy S; Lopez, Oscar; Cushman, Mary; Olson, Nels C; Fitzpatrick, Annette; Mukamal, Kenneth J; Jensen, Majken K (Thromb Res, 2024)
INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.
Keywords: Aged; Anticoagulants; Antithrombin III; Antithrombins; Dementia; Factor VIIa; Fibrinogen; Hemostatics; Humans; Prospective Studies; Thrombin

Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations. - Lundin, Jessica I; Peters, Ulrike; Hu, Yao; Ammous, Farah; Avery, Christy L; Benjamin, Emelia J; Bis, Joshua C; Brody, Jennifer A; Carlson, Chris; Cushman, Mary; Gignoux, Chris; Guo, Xiuqing; et al. (Epigenetics, 2024)
Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total  = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (, , and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level ( < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of and CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with , , and . Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.
Keywords: C-Reactive Protein; CpG Islands; DNA; DNA Methylation; Epigenesis, Genetic; Genome-Wide Association Study; Humans; Inflammation; Intracellular Signaling Peptides and Proteins

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. - Mei, Hao; Simino, Jeannette; Li, Lianna; Jiang, Fan; Bis, Joshua C; Davies, Gail; Hill, W David; Xia, Charley; Gudnason, Vilmundur; Yang, Qiong; Lahti, Jari; Smith, Jennifer A; et al. (Alzheimers Res Ther, 2024)
BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
Keywords: Aged; Cognition; Genome-Wide Association Study; Humans; Memory; MicroRNAs; Multiomics; Polymorphism, Single Nucleotide

{Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications - Sterenborg, R. B. T. M.; Steinbrenner, I.; Li, Y.; Bujnis, M. N.; Naito, T.; Marouli, E.; Galesloot, T. E.; Babajide, O.; Andreasen, L.; Astrup, A.; svold, B. O.; Bandinelli, S.; et al. (Nat Commun, 2024)
T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Plasma proteomic signature of human longevity. - Liu, Xiaojuan; Axelsson, Gisli Thor; Newman, Anne B; Psaty, Bruce M; Boudreau, Robert M; Wu, Chenkai; Arnold, Alice M; Aspelund, Thor; Austin, Thomas R; Gardin, Julius M; Siggeirsdottir, Kristin; Tracy, Russell P; et al. (Aging Cell, 2024)
The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure. - Alkis, Taryn; Luo, Xi; Wall, Katherine; Brody, Jennifer; Bartz, Traci; Chang, Patricia P; Norby, Faye L; Hoogeveen, Ron C; Morrison, Alanna C; Ballantyne, Christie M; Coresh, Josef; Boerwinkle, Eric; et al. (ESC Heart Fail, 2024)
AIMS: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations. METHODS AND RESULTS: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS . CONCLUSIONS: The PRS was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. - Laguzzi, Federica; Åkesson, Agneta; Marklund, Matti; Qian, Frank; Gigante, Bruna; Bartz, Traci M; Bassett, Julie K; Birukov, Anna; Campos, Hannia; Hirakawa, Yoichiro; Imamura, Fumiaki; Jäger, Susanne; et al. (Circulation, 2024)
BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.
Keywords: Animals; Biomarkers; Cardiovascular Diseases; Docosahexaenoic Acids; Fatty Acids, Omega-3; Risk Factors

Trajectory of Cognitive Function After Incident Heart Failure. - Shore, Supriya; Li, Hanyu; Zhang, Min; Whitney, Rachael; Gross, Alden L; Bhatt, Ankeet S; Nallamothu, Brahmajee K; Giordani, Bruno; Briceño, Emily M; Sussman, Jeremy B; Gutierrez, Jose; Yaffe, Kristine; et al. (medRxiv, 2024)
BACKGROUND: The size/magnitude of cognitive changes after incident heart failure (HF) are unclear. We assessed whether incident HF is associated with changes in cognitive function after accounting for pre-HF cognitive trajectories and known determinants of cognition. METHODS: This pooled cohort study included adults without HF, stroke, or dementia from six US population-based cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), controlling for pre-HF cognitive trajectories and participant factors. Change in global cognition was the primary outcome. Change in executive function and memory were secondary outcomes. Cognitive outcomes were standardized to a -score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. RESULTS: The study included 29,614 adults (mean [SD] age was 61.1 [10.5] years, 55% female, 70.3% White, 22.2% Black 7.5% Hispanic). During a median follow-up of 6.6 (Q1-Q3: 5-19.8) years, 1,407 (4.7%) adults developed incident HF. Incident HF was associated with an acute decrease in global cognition (-1.08 points; 95% CI -1.36, -0.80) and executive function (-0.65 points; 95% CI -0.96, -0.34) but not memory (-0.51 points; 95% CI -1.37, 0.35) at the time of the event. Greater acute decreases in global cognition after HF were seen in those with older age, female sex and White race. Individuals with incident HF, compared to HF-free individuals, demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21, -0.09) and executive function (-0.16 points per year; 95% CI -0.23, -0.09) but not memory ( -0.11 points per year; 95% CI -0.26, 0.04) compared with pre-HF slopes. CONCLUSIONS: In this pooled cohort study, incident HF was associated with an acute decrease in global cognition and executive function at the time of the event and faster declines in global cognition and executive function over the following years.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. - Scholz, Markus; Horn, Katrin; Pott, Janne; Wuttke, Matthias; Kühnapfel, Andreas; Nasr, M Kamal; Kirsten, Holger; Li, Yong; Hoppmann, Anselm; Gorski, Mathias; Ghasemi, Sahar; Li, Man; et al. (Nat Commun, 2024)
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
Keywords: Androgens; Chromosomes, Human, X; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Kidney; Male; Polymorphism, Single Nucleotide; Response Elements; Tetraspanins