@article {1124, title = {Total and cause-specific mortality in the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1251-61}, abstract = {

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cause of Death, Chronic Disease, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Kaplan-Meier Estimate, Male, Probability, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp127}, author = {Newman, Anne B and Sachs, Michael C and Arnold, Alice M and Fried, Linda P and Kronmal, Richard and Cushman, Mary and Psaty, Bruce M and Harris, Tamara B and Robbins, John A and Burke, Gregory L and Kuller, Lewis H and Lumley, Thomas} } @article {7246, title = {Targeted Sequencing of Genome Wide Significant Loci Associated with Bone Mineral Density (BMD) Reveals Significant Novel and Rare Variants: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.}, journal = {Hum Mol Genet}, year = {2016}, month = {2016 Sep 11}, abstract = {

BACKGROUND: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis.

METHODS AND RESULTS: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n=925) and Cardiovascular Health Study (n=366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80\% were rare with MAF <1\%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5{\textquoteright} of MEF2C (p-values < 8x10(-5); false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements.

CONCLUSIONS: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddw289}, author = {Hsu, Yi-Hsiang and Li, Guo and Liu, Ching-Ti and Brody, Jennifer A and Karasik, David and Chou, Wen-Chi and Demissie, Serkalem and Nandakumar, Kannabiran and Zhou, Yanhua and Cheng, Chia-Ho and Gill, Richard and Gibbs, Richard A and Muzny, Donna and Santibanez, Jireh and Estrada, Karol and Rivadeneira, Fernando and Harris, Tamara and Gudnason, Vilmundur and Uitterlinden, Andre and Psaty, Bruce M and Robbins, John A and Adrienne Cupples, L and Kiel, Douglas P} } @article {9089, title = {Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.}, journal = {Bone}, volume = {161}, year = {2022}, month = {2022 08}, pages = {116431}, abstract = {

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}, issn = {1873-2763}, doi = {10.1016/j.bone.2022.116431}, author = {Elam, Rachel E and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Wang, Zeneng and Nemet, Ina and Budoff, Matthew J and Cauley, Jane A and Fink, Howard A and Lee, Yujin and Robbins, John A and Wang, Meng and Hazen, Stanley L and Mozaffarian, Dariush and Carbone, Laura D} }