03001nas a2200397 4500008004100000022001400041245012100055210006900176260001300245300001300258490000700271520187200278653001002150653000902160653002202169653002802191653001702219653002802236653001102264653002202275653002002297653001102317653001402328653000902342653002302351100002002374700002102394700002502415700002402440700002002464700002002484700002402504700002002528700001902548856003602567 2015 eng d a1523-468100aAssociation of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.0 aAssociation of FetuinA With Incident Fractures in CommunityDwell c2015 Aug a1394-4020 v303 a

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women ≥65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.

10aAdult10aAged10aAged, 80 and over10aalpha-2-HS-Glycoprotein10aBone Density10aCross-Sectional Studies10aFemale10aFollow-Up Studies10aFractures, Bone10aHumans10aIncidence10aMale10aModels, Biological1 aFink, Howard, A1 aBůzková, Petra1 aGarimella, Pranav, S1 aMukamal, Kenneth, J1 aCauley, Jane, A1 aKizer, Jorge, R1 aBarzilay, Joshua, I1 aJalal, Diana, I1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/666602027nas a2200217 4500008004100000022001400041245012700055210006900182260001500251300001600266490000700282520132500289100002301614700002101637700002401658700003001682700002101712700002001733700002001753856003601773 2020 eng d a1945-458900aAssociation of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.0 aAssociation of skeletal muscle mass kidney disease and mortality c2020 11 02 a21023-210360 v123 a

Low muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m/year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.

1 aKruse, Nicholas, T1 aBůzková, Petra1 aBarzilay, Joshua, I1 aValderrábano, Rodrigo, J1 aRobbins, John, A1 aFink, Howard, A1 aJalal, Diana, I uhttps://chs-nhlbi.org/node/862703396nas a2200433 4500008004100000022001400041245015600055210006900211260001600280520204800296100002202344700002002366700002002386700002402406700002102430700002402451700001702475700001902492700002602511700002102537700002002558700002402578700002002602700002302622700002402645700002402669700002102693700002002714700002102734700001602755700002602771700002602797700003002823700001502853700002002868700001902888700001902907856003602926 2024 eng d a1523-468100aLarge-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.0 aLargescale circulating proteome association study CPAS metaanaly c2024 Jan 043 a

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.

1 aAustin, Thomas, R1 aFink, Howard, A1 aJalal, Diana, I1 aTörnqvist, Anna, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aLu, Tianyuan1 aCarbone, Laura1 aGabrielsen, Maiken, E1 aGrahnemo, Louise1 aHveem, Kristian1 aJonasson, Christian1 aKizer, Jorge, R1 aLanghammer, Arnulf1 aMukamal, Kenneth, J1 aGerszten, Robert, E1 aNethander, Maria1 aPsaty, Bruce, M1 aRobbins, John, A1 aSun, Yan, V1 aSkogholt, Anne, Heidi1 aÅsvold, Bjørn, Olav1 aValderrábano, Rodrigo, J1 aZheng, Jie1 aRichards, Brent1 aCoward, Eivind1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/9635