%0 Journal Article %J J Am Geriatr Soc %D 2006 %T Adjusted mortality after hip fracture: From the cardiovascular health study. %A Robbins, John A %A Biggs, Mary L %A Cauley, Jane %K Aged %K Cohort Studies %K Female %K Health Status %K Health Surveys %K Hip Fractures %K Humans %K Male %K Mortality %K Multicenter Studies as Topic %K Proportional Hazards Models %K Sex Distribution %K Time Factors %K United States %X

OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture.

DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment.

SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites.

PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx.

MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health.

RESULTS: Age- and race-adjusted excess mortality was 9% in women and 24% in men 1 year after fracture, and 24% in women and 26% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95% confidence interval (CI) = 2.3-21.5), 2.1 (95% CI = 1.0-4.1), 1.4 (95% CI = 1.1-2.0), and 1.0 (95% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95% CI = 5.2-308.7), 3.8 (95% CI = 1.4-10.3), 1.1 (95% CI = 0.7-1.8), and 1.0 (95% CI = 0.3-2.7). HRs adjusted for age and race were 20% to 40% higher.

CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.

%B J Am Geriatr Soc %V 54 %P 1885-91 %8 2006 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/17198494?dopt=Abstract %R 10.1111/j.1532-5415.2006.00985.x %0 Journal Article %J Obesity (Silver Spring) %D 2007 %T Alcohol consumption and type 2 diabetes among older adults: the Cardiovascular Health Study. %A Djoussé, Luc %A Biggs, Mary L %A Mukamal, Kenneth J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Medicare %K Middle Aged %K Risk %K Smoking %K Temperance %K United States %X

OBJECTIVE: The objective was to examine the role of total and beverage-specific alcohol consumption on the incidence of type 2 diabetes mellitus (DM) among elderly men and women.

RESEARCH METHODS AND PROCEDURES: We studied prospectively 4655 participants of the Cardiovascular Health Study who were free of DM at baseline. Alcohol consumption was obtained at baseline and during follow-up examinations. DM was defined using fasting glucose and/or use of hypoglycemic medications. We used Cox proportional hazard models to estimate adjusted relative risks of diabetes across alcohol categories.

RESULTS: During a mean follow-up of 6.3 years, 234 incident cases of DM were documented. Compared with never drinkers, hazard ratios [95% confidence interval (CI)] for DM were 0.7 (0.3 to 1.4), 0.5 (0.3 to 0.9), 0.6 (0.4 to 1.1), and 0.8 (0.4 to 1.3) for former drinkers and current drinkers of <1, 1 to 6, and 7+ drinks per week, respectively, for men after adjustment for age, BMI, education, and smoking. Corresponding values for women were 1.2 (0.6 to 2.3), 0.7 (0.4 to 1.1), 0.6 (0.3 to 1.1), and 0.4 (0.2 to 1.0), respectively. A reduced risk of DM was observed with all types of beverage consumed. Similar findings were observed when we repeated the above analyses using simple or weighted cumulative alcohol update and covariates over time.

DISCUSSION: Light to moderate alcohol consumption was associated with a lower incidence of DM among elderly people, irrespective of the type of beverage consumed.

%B Obesity (Silver Spring) %V 15 %P 1758-65 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17636094?dopt=Abstract %R 10.1038/oby.2007.209 %0 Journal Article %J Arch Intern Med %D 2007 %T Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. %A Carnethon, Mercedes R %A Biggs, Mary L %A Barzilay, Joshua I %A Smith, Nicholas L %A Vaccarino, Viola %A Bertoni, Alain G %A Arnold, Alice %A Siscovick, David %K Aged %K Body Mass Index %K C-Reactive Protein %K Depression %K Diabetes Mellitus, Type 2 %K Drinking %K Female %K Humans %K Longitudinal Studies %K Male %K Smoking %X

BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus.

METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681).

RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95% confidence interval, 1.1-2.3]).

CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.

%B Arch Intern Med %V 167 %P 802-7 %8 2007 Apr 23 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/17452543?dopt=Abstract %R 10.1001/archinte.167.8.802 %0 Journal Article %J Atherosclerosis %D 2008 %T Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study. %A Cao, Jie J %A Biggs, Mary L %A Barzilay, Joshua %A Konen, Joseph %A Psaty, Bruce M %A Kuller, Lewis %A Bleyer, Anthony J %A Olson, Jean %A Wexler, Jason %A Summerson, John %A Cushman, Mary %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Cohort Studies %K Coronary Disease %K Cross-Sectional Studies %K Female %K Health Surveys %K Humans %K Male %K Predictive Value of Tests %K Risk %X

BACKGROUND: Elevated urinary albumin excretion (UAE) is associated with the risk of cardiovascular disease (CVD) and all-cause mortality. We tested the hypothesis that elevated UAE improves cardiovascular risk stratification in an elderly cohort aged 68-102 years.

METHODS: We evaluated UAE in 3112 participants of the Cardiovascular Health Study who attended the 1996-1997 examination and had median follow up of 5.4 years. Elevated UAE was defined as urinary albumin to creatinine ratio > or =30 microg/mg. Microalbuminuria and macroalbuminuria were defined as urinary albumin to creatinine ratio 30-300 microg/mg and >300 microg/mg, respectively. Outcomes included CVD (myocardial infarction, stroke, cardiovascular death) and all-cause mortality. Cox proportional hazards models were used to assess the risk of outcomes associated with elevated UAE.

RESULTS: The prevalence of elevated UAE was 14.3%, 17.1% and 26.9% in those aged 68-74, 75-84 and 85-102 years, respectively. CVD incidence and all-cause mortality were doubled (7.2% and 8.1% per year) in those with microalbuminuria and tripled (11.1% and 12.3% per year) in those with macroalbuminuria compared to those with normal UAE (3.3% and 3.8% per year). The increased CVD and mortality risks were observed in all age groups after adjustment for conventional risk factors. The adjusted population attributable risk percent of CVD and all-cause mortality for elevated UAE was 11% and 12%, respectively. When participants were cross-classified by UAE and Framingham Risk Score categories, the 5-year cumulative incidence of coronary heart disease among participants with elevated UAE and a 5-year predicted risk of 5-10% was 20%, substantially higher than 6.3% in those with UAE <30m microg/mg.

CONCLUSION: Elevated UAE was associated with an increased risk of CVD and all-cause mortality in all age groups from 68 to 102 years. Combining elevated UAE with the Framingham risk scores may improve risk stratification for CVD in the elderly.

%B Atherosclerosis %V 197 %P 806-13 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17875308?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.07.029 %0 Journal Article %J Cancer Causes Control %D 2009 %T C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. %A Pierce, Brandon L %A Biggs, Mary L %A DeCambre, Marvalyn %A Reiner, Alexander P %A Li, Christopher %A Fitzpatrick, Annette %A Carlson, Christopher S %A Stanford, Janet L %A Austin, Melissa A %K African Americans %K Aged %K Aged, 80 and over %K Biomarkers %K C-Reactive Protein %K European Continental Ancestry Group %K Humans %K Inflammation %K Interleukin-6 %K Male %K Polymorphism, Single Nucleotide %K Prospective Studies %K Prostatic Neoplasms %K Risk Factors %X

Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and the subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men of ages >64 years (n = 2,234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs that are known to associate with circulating CRP and/or IL-6. Neither CRP nor IL-6 blood concentrations was associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR = 1.44; 95% CI = 1.03-2.01; p = 0.03), but was not statistically significant after accounting for multiple tests (permutation p = 0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.

%B Cancer Causes Control %V 20 %P 1193-203 %8 2009 Sep %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/19267250?dopt=Abstract %R 10.1007/s10552-009-9320-4 %0 Journal Article %J JAMA %D 2010 %T Association between adiposity in midlife and older age and risk of diabetes in older adults. %A Biggs, Mary L %A Mukamal, Kenneth J %A Luchsinger, José A %A Ix, Joachim H %A Carnethon, Mercedes R %A Newman, Anne B %A de Boer, Ian H %A Strotmeyer, Elsa S %A Mozaffarian, Dariush %A Siscovick, David S %K Adiposity %K Age Factors %K Aged %K Body Mass Index %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Male %K Prospective Studies %K Risk Factors %K United States %K Weight Gain %X

CONTEXT: Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.

OBJECTIVE: To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.

DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.

MAIN OUTCOME MEASURE: Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.

RESULTS: Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+/-2 kg), those who gained the most weight from 50 years of age to baseline (> or = 9 kg), and from baseline to the third follow-up visit (> or = 6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.

CONCLUSION: Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.

%B JAMA %V 303 %P 2504-12 %8 2010 Jun 23 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/20571017?dopt=Abstract %R 10.1001/jama.2010.843 %0 Journal Article %J Am J Med %D 2010 %T Diabetes and coronary heart disease as risk factors for mortality in older adults. %A Carnethon, Mercedes R %A Biggs, Mary L %A Barzilay, Joshua %A Kuller, Lewis H %A Mozaffarian, Dariush %A Mukamal, Kenneth %A Smith, Nicholas L %A Siscovick, David %K Aged %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Male %K Prevalence %K Risk Factors %K Sex Distribution %K Survival Rate %K Time Factors %K United States %X

BACKGROUND: Type 2 diabetes has been described as a coronary heart disease (CHD) "risk equivalent." We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common.

METHODS: The Cardiovascular Health Study is a longitudinal study of men and women (n=5784) aged > or =65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose > or =7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization.

RESULTS: Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent=8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone.

CONCLUSIONS: Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.

%B Am J Med %V 123 %P 556.e1-9 %8 2010 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20569763?dopt=Abstract %R 10.1016/j.amjmed.2009.11.023 %0 Journal Article %J PLoS One %D 2010 %T Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. %A Gkrania-Klotsas, Effrossyni %A Ye, Zheng %A Cooper, Andrew J %A Sharp, Stephen J %A Luben, Robert %A Biggs, Mary L %A Chen, Liang-Kung %A Gokulakrishnan, Kuppan %A Hanefeld, Markolf %A Ingelsson, Erik %A Lai, Wen-An %A Lin, Shih-Yi %A Lind, Lars %A Lohsoonthorn, Vitool %A Mohan, Viswanathan %A Muscari, Antonio %A Nilsson, Goran %A Ohrvik, John %A Chao Qiang, Jiang %A Jenny, Nancy Swords %A Tamakoshi, Koji %A Temelkova-Kurktschiev, Theodora %A Wang, Ya-Yu %A Yajnik, Chittaranjan Sakerlal %A Zoli, Marco %A Khaw, Kay-Tee %A Forouhi, Nita G %A Wareham, Nicholas J %A Langenberg, Claudia %K Adult %K Aged %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Leukocyte Count %K Male %K Middle Aged %K Prospective Studies %X

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

%B PLoS One %V 5 %P e13405 %8 2010 Oct 18 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract %R 10.1371/journal.pone.0013405 %0 Journal Article %J PLoS One %D 2010 %T Polymorphisms in the mitochondrial DNA control region and frailty in older adults. %A Moore, Ann Z %A Biggs, Mary L %A Matteini, Amy %A O'Connor, Ashley %A McGuire, Sarah %A Beamer, Brock A %A Fallin, M Danielle %A Fried, Linda P %A Walston, Jeremy %A Chakravarti, Aravinda %A Arking, Dan E %K Aged %K Aged, 80 and over %K DNA, Mitochondrial %K Female %K Frail Elderly %K Genotype %K Humans %K Male %K Polymorphism, Genetic %X

BACKGROUND: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.

METHODOLOGY/PRINCIPAL FINDINGS: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002).

CONCLUSIONS: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.

%B PLoS One %V 5 %P e11069 %8 2010 Jun 10 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20548781?dopt=Abstract %R 10.1371/journal.pone.0011069 %0 Journal Article %J Am J Epidemiol %D 2011 %T Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study. %A Ix, Joachim H %A Biggs, Mary L %A Kizer, Jorge R %A Mukamal, Kenneth J %A Djoussé, Luc %A Zieman, Susan J %A de Boer, Ian H %A Nelson, Tracy L %A Newman, Anne B %A Criqui, Michael H %A Siscovick, David S %K Aged %K Ankle Brachial Index %K Body Mass Index %K Cross-Sectional Studies %K Health Status %K Humans %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Obesity %K Peripheral Arterial Disease %K Prevalence %K Sex Factors %K Smoking %K United States %X

The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥ 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.

%B Am J Epidemiol %V 174 %P 1036-43 %8 2011 Nov 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21920948?dopt=Abstract %R 10.1093/aje/kwr228 %0 Journal Article %J J Alzheimers Dis %D 2011 %T Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study. %A Arab, Lenore %A Biggs, Mary L %A O'Meara, Ellen S %A Longstreth, W T %A Crane, Paul K %A Fitzpatrick, Annette L %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coffee %K Cognition Disorders %K Cohort Studies %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Prospective Studies %K Sex Characteristics %K Tea %X

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

%B J Alzheimers Dis %V 27 %P 553-66 %8 2011 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21841254?dopt=Abstract %R 10.3233/JAD-2011-110431 %0 Journal Article %J Am J Epidemiol %D 2011 %T Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women. %A Kizer, Jorge R %A Biggs, Mary L %A Ix, Joachim H %A Mukamal, Kenneth J %A Zieman, Susan J %A de Boer, Ian H %A Mozaffarian, Dariush %A Barzilay, Joshua I %A Strotmeyer, Elsa S %A Luchsinger, José A %A Elkind, Mitchell S V %A Longstreth, W T %A Kuller, Lewis H %A Siscovick, David S %K Adiposity %K Age Factors %K Aged %K Aged, 80 and over %K Brain Ischemia %K Coronary Disease %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Obesity %K Prevalence %K Retrospective Studies %K Risk Factors %K Sex Factors %K United States %X

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥ 30 kg/m²) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m² was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

%B Am J Epidemiol %V 173 %P 10-25 %8 2011 Jan 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21123850?dopt=Abstract %R 10.1093/aje/kwq311 %0 Journal Article %J Am J Clin Nutr %D 2011 %T Plasma omega-3 fatty acids and incident diabetes in older adults. %A Djoussé, Luc %A Biggs, Mary L %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Ix, Joachim H %A Mukamal, Kenneth J %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K alpha-Linolenic Acid %K Diabetes Mellitus %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %X

BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs.

OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes.

DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks.

RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03).

CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.

%B Am J Clin Nutr %V 94 %P 527-33 %8 2011 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21593500?dopt=Abstract %R 10.3945/ajcn.111.013334 %0 Journal Article %J Circulation %D 2012 %T Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. %A Ix, Joachim H %A Biggs, Mary L %A Mukamal, Kenneth J %A Kizer, Jorge R %A Zieman, Susan J %A Siscovick, David S %A Mozzaffarian, Dariush %A Jensen, Majken K %A Nelson, Lauren %A Ruderman, Neil %A Djoussé, Luc %K African Continental Ancestry Group %K Age Distribution %K Aged %K Aged, 80 and over %K alpha-2-HS-Glycoprotein %K Body Mass Index %K C-Reactive Protein %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Humans %K Incidence %K Life Style %K Lipids %K Male %K Pilot Projects %K Prevalence %K Proportional Hazards Models %K Residence Characteristics %K Risk Factors %K Sex Distribution %X

BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD).

METHODS AND RESULTS: Among 3710 community-living individuals ≥ 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01).

CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those ≥ 75 years of age.

%B Circulation %V 125 %P 2316-22 %8 2012 May 15 %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/22511752?dopt=Abstract %R 10.1161/CIRCULATIONAHA.111.072751 %0 Journal Article %J JAMA %D 2012 %T Association of weight status with mortality in adults with incident diabetes. %A Carnethon, Mercedes R %A De Chavez, Peter John D %A Biggs, Mary L %A Lewis, Cora E %A Pankow, James S %A Bertoni, Alain G %A Golden, Sherita H %A Liu, Kiang %A Mukamal, Kenneth J %A Campbell-Jenkins, Brenda %A Dyer, Alan R %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K Body Weight %K Cardiovascular Diseases %K Cause of Death %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Obesity %K Overweight %K United States %X

CONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences.

OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality.

DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater.

MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality.

RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively.

CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.

%B JAMA %V 308 %P 581-90 %8 2012 Aug 08 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22871870?dopt=Abstract %R 10.1001/jama.2012.9282 %0 Journal Article %J Clin J Am Soc Nephrol %D 2012 %T Chronic kidney disease, insulin resistance, and incident diabetes in older adults. %A Pham, Hien %A Robinson-Cohen, Cassianne %A Biggs, Mary L %A Ix, Joachim H %A Mukamal, Kenneth J %A Fried, Linda F %A Kestenbaum, Bryan %A Siscovick, David S %A de Boer, Ian H %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Chronic Disease %K Creatinine %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Glucose Tolerance Test %K Health Surveys %K Humans %K Hypoglycemic Agents %K Incidence %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Kidney %K Kidney Diseases %K Linear Models %K Male %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K United States %X

BACKGROUND AND OBJECTIVES: Insulin resistance is a complication of advanced CKD. Insulin resistance is less well characterized in earlier stages of CKD. The response of the pancreatic β cell, effects on glucose tolerance, and risk of diabetes are not clear.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Health Study included 4680 adults without baseline diabetes. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation was used to obtain the estimated GFR (eGFR). Insulin resistance was evaluated as fasting insulin concentration. The insulin sensitivity index, β cell function, and glucose tolerance were assessed by oral glucose tolerance testing. Incident diabetes was defined as fasting glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or use of glucose-lowering medications.

RESULTS: Mean age was 72.5 years (range, 65-98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m(2). After adjustment, each 10 ml/min per 1.73 m(2) lower eGFR was associated with a 2.2% higher fasting insulin concentration (95% confidence interval [CI], 1.4%, 2.9%; P<0.001) and a 1.1% lower insulin sensitivity index (95% CI, 0.03%, 2.2%; P=0.04). Surprisingly, eGFR was associated with an augmented β cell function index (P<0.001), lower 2-hour glucose concentration (P=0.002), and decreased risk of glucose intolerance (P=0.006). Over a median 12 years' follow-up, 437 participants (9.3%) developed diabetes. eGFR was not associated with the risk of incident diabetes.

CONCLUSIONS: Among older adults, lower eGFR was associated with insulin resistance. However, with lower eGFR, β cell function was appropriately augmented and risks of impaired glucose tolerance and incident diabetes were not increased.

%B Clin J Am Soc Nephrol %V 7 %P 588-94 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22383749?dopt=Abstract %R 10.2215/CJN.11861111 %0 Journal Article %J PLoS One %D 2012 %T Hemoglobin A1c and arterial and ventricular stiffness in older adults. %A Zieman, Susan J %A Kamineni, Aruna %A Ix, Joachim H %A Barzilay, Joshua %A Djoussé, Luc %A Kizer, Jorge R %A Biggs, Mary L %A de Boer, Ian H %A Chonchol, Michel %A Gottdiener, John S %A Selvin, Elizabeth %A Newman, Anne B %A Kuller, Lewis H %A Siscovick, David S %A Mukamal, Kenneth J %K Adult %K African Continental Ancestry Group %K Aged %K Ankle Brachial Index %K Arteries %K Blood Glucose %K Blood Pressure %K Body Mass Index %K Cross-Sectional Studies %K Fasting %K Female %K Genetic Association Studies %K Glycated Hemoglobin A %K Glycation End Products, Advanced %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Ultrasonography %K Vascular Stiffness %X

OBJECTIVE: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.

RESEARCH DESIGN & METHODS: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥ 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.

RESULTS: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.

CONCLUSIONS: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.

%B PLoS One %V 7 %P e47941 %8 2012 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/23118911?dopt=Abstract %R 10.1371/journal.pone.0047941 %0 Journal Article %J Vasc Med %D 2012 %T Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study. %A Britton, Kathryn A %A Mukamal, Kenneth J %A Ix, Joachim H %A Siscovick, David S %A Newman, Anne B %A de Boer, Ian H %A Thacker, Evan L %A Biggs, Mary L %A Gaziano, J Michael %A Djoussé, Luc %K Aged %K Ankle Brachial Index %K Biomarkers %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Diabetic Angiopathies %K Fasting %K Female %K Health Surveys %K Humans %K Incidence %K Insulin %K Insulin Resistance %K Logistic Models %K Longitudinal Studies %K Male %K Odds Ratio %K Peripheral Arterial Disease %K Predictive Value of Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

Type 2 diabetes is a risk factor for peripheral artery disease (PAD), and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by two methods. PAD was first defined as the development of an abnormal ankle-brachial index (ABI) (dichotomous outcome) after 6 years of follow-up. PAD was alternatively defined as the development of clinical PAD (time-to-event analysis). The study samples included adults over the age of 65 years who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, body mass index (BMI), smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n = 2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (odds ratio = 1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval [CI] 1.20-2.71). In the clinical PAD analysis (n = 4208), we found a similar relation (hazard ratio = 2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% CI 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.

%B Vasc Med %V 17 %P 85-93 %8 2012 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22402937?dopt=Abstract %R 10.1177/1358863X11436195 %0 Journal Article %J Parkinsonism Relat Disord %D 2012 %T Markers of inflammation in prevalent and incident Parkinson's disease in the Cardiovascular Health Study. %A Ton, Thanh G N %A Jain, Samay %A Biggs, Mary L %A Thacker, Evan L %A Strotmeyer, Elsa S %A Boudreau, Robert %A Newman, Anne B %A Longstreth, W T %A Checkoway, Harvey %K Aged %K Aged, 80 and over %K Albumins %K Biomarkers %K C-Reactive Protein %K Enzyme-Linked Immunosorbent Assay %K Female %K Fibrinogen %K Humans %K Incidence %K Inflammation %K Interleukin-6 %K Leukocyte Count %K Male %K Parkinson Disease %K Prevalence %K Risk Factors %K Tumor Necrosis Factor-alpha %X

BACKGROUND: Studies demonstrate existence of inflammation in prevalent Parkinson's disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.

METHODS: Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.

RESULTS: Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR]=1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).

CONCLUSIONS: Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.

%B Parkinsonism Relat Disord %V 18 %P 274-8 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22119505?dopt=Abstract %R 10.1016/j.parkreldis.2011.11.003 %0 Journal Article %J Circ Arrhythm Electrophysiol %D 2012 %T Nonesterified fatty acids and risk of sudden cardiac death in older adults. %A Djoussé, Luc %A Biggs, Mary L %A Ix, Joachim H %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Sotoodehnia, Nona %A Zieman, Susan J %A Mozaffarian, Dariush %A Tracy, Russell P %A Mukamal, Kenneth J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Biomarkers %K Death, Sudden, Cardiac %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Prospective Studies %K Retrospective Studies %K Risk Factors %X

BACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.

METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.

CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.

%B Circ Arrhythm Electrophysiol %V 5 %P 273-8 %8 2012 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22281952?dopt=Abstract %R 10.1161/CIRCEP.111.967661 %0 Journal Article %J Diabetes Care %D 2012 %T Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults. %A Djoussé, Luc %A Khawaja, Owais %A Bartz, Traci M %A Biggs, Mary L %A Ix, Joachim H %A Zieman, Susan J %A Kizer, Jorge R %A Tracy, Russell P %A Siscovick, David S %A Mukamal, Kenneth J %K Aged %K Aged, 80 and over %K Blood Glucose %K Body Mass Index %K Diabetes Mellitus %K Fatty Acid-Binding Proteins %K Fatty Acids, Nonesterified %K Female %K Humans %K Male %K Prospective Studies %X

OBJECTIVE: To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.

RESEARCH DESIGN AND METHODS: We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose ≥ 126 mg/dL, or nonfasting glucose ≥ 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.

RESULTS: Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03).

CONCLUSIONS: Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.

%B Diabetes Care %V 35 %P 1701-7 %8 2012 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22584136?dopt=Abstract %R 10.2337/dc11-1690 %0 Journal Article %J Ann Intern Med %D 2012 %T Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. %A de Boer, Ian H %A Levin, Gregory %A Robinson-Cohen, Cassianne %A Biggs, Mary L %A Hoofnagle, Andy N %A Siscovick, David S %A Kestenbaum, Bryan %K Aged %K Cause of Death %K Female %K Follow-Up Studies %K Hip Fractures %K Humans %K Male %K Myocardial Infarction %K Neoplasms %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Seasons %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.

OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.

PARTICIPANTS: 1621 white older adults.

MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.

RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.

LIMITATION: The observational study was restricted to white participants.

CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.

PRIMARY FUNDING SOURCE: National Institutes of Health.

%B Ann Intern Med %V 156 %P 627-34 %8 2012 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22547472?dopt=Abstract %R 10.7326/0003-4819-156-9-201205010-00004 %0 Journal Article %J Neuroepidemiology %D 2013 %T Adiposity and cognitive decline in the cardiovascular health study. %A Luchsinger, José A %A Biggs, Mary L %A Kizer, Jorge R %A Barzilay, Joshua %A Fitzpatrick, Annette %A Newman, Anne %A Longstreth, William T %A Lopez, Oscar %A Siscovick, David %A Kuller, Lewis %K Adiposity %K Aged %K Aged, 80 and over %K Body Mass Index %K Cardiovascular Diseases %K Cognition Disorders %K Electric Impedance %K Female %K Humans %K Male %K Risk Factors %K Waist Circumference %K Waist-Hip Ratio %X

BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.

METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.

RESULTS: The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.

CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

%B Neuroepidemiology %V 40 %P 274-81 %8 2013 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23445925?dopt=Abstract %R 10.1159/000345136 %0 Journal Article %J Metabolism %D 2013 %T Circulating 25-hydroxyvitamin D is associated with insulin resistance cross-sectionally but not longitudinally in older adults: The Cardiovascular Health Study. %A Danziger, John %A Biggs, Mary L %A Niemi, Matt %A Ix, Joachim H %A Kizer, Jorge R %A Djoussé, Luc %A de Boer, Ian H %A Siscovick, David S %A Kestenbaum, Bryan %A Mukamal, Kenneth J %K Adiposity %K Aged %K Anthropometry %K Cardiovascular Diseases %K Cross-Sectional Studies %K Exercise %K Female %K Humans %K Hydroxycholecalciferols %K Inflammation %K Insulin %K Insulin Resistance %K Longitudinal Studies %K Male %K Middle Aged %K Obesity %K Risk Factors %K Surveys and Questionnaires %X

BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.

OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.

METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.

CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.

%B Metabolism %V 62 %P 1788-94 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23987236?dopt=Abstract %R 10.1016/j.metabol.2013.07.008 %0 Journal Article %J Lipids %D 2013 %T Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. %A Mukamal, Kenneth J %A Wilk, Jemma B %A Biggs, Mary L %A Jensen, Majken K %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell P %A Zieman, Susan J %A Mozaffarian, Dariush %A Psaty, Bruce M %A Siscovick, David S %A Djoussé, Luc %K African Americans %K Aged %K Aged, 80 and over %K Blood Glucose %K Body Mass Index %K Cohort Studies %K European Continental Ancestry Group %K Fatty Acid-Binding Proteins %K Female %K Gene Frequency %K Genetic Association Studies %K Haplotypes %K Humans %K Insulin %K Linkage Disequilibrium %K Male %K Polymorphism, Single Nucleotide %X

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

%B Lipids %V 48 %P 1169-75 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24043587?dopt=Abstract %R 10.1007/s11745-013-3838-7 %0 Journal Article %J Circ Heart Fail %D 2013 %T Insulin resistance and risk of incident heart failure: Cardiovascular Health Study. %A Banerjee, Dipanjan %A Biggs, Mary L %A Mercer, Laina %A Mukamal, Kenneth %A Kaplan, Robert %A Barzilay, Joshua %A Kuller, Lewis %A Kizer, Jorge R %A Djoussé, Luc %A Tracy, Russell %A Zieman, Susan %A Lloyd-Jones, Donald %A Siscovick, David %A Carnethon, Mercedes %K Aged %K Female %K Heart Atria %K Heart Failure %K Heart Ventricles %K Humans %K Incidence %K Insulin %K Insulin Resistance %K Male %K Middle Aged %K Myocardial Infarction %K Organ Size %K Proportional Hazards Models %K Prospective Studies %X

BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease.

METHODS AND RESULTS: We examined 4425 participants (60% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin).

CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

%B Circ Heart Fail %V 6 %P 364-70 %8 2013 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23575256?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.112.000022 %0 Journal Article %J Cardiol Res Pract %D 2013 %T Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults. %A Djoussé, Luc %A Maziarz, Marlena %A Biggs, Mary L %A Ix, Joachim H %A Zieman, Susan J %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %A Tracy, Russell P %A Mukamal, Kenneth J %A Siscovick, David S %A Sotoodehnia, Nona %X

Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

%B Cardiol Res Pract %V 2013 %P 181054 %8 2013 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24455402?dopt=Abstract %R 10.1155/2013/181054 %0 Journal Article %J Circ Arrhythm Electrophysiol %D 2014 %T Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study. %A Agarwal, Isha %A Glazer, Nicole L %A Barasch, Eddy %A Biggs, Mary L %A Djoussé, Luc %A Fitzpatrick, Annette L %A Gottdiener, John S %A Ix, Joachim H %A Kizer, Jorge R %A Rimm, Eric B %A Sicovick, David S %A Tracy, Russell P %A Mukamal, Kenneth J %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Female %K Fibrosis %K Heart Failure %K Humans %K Incidence %K Male %K Myocardial Infarction %K Peptide Fragments %K Procollagen %K Prognosis %K Prospective Studies %K Risk Assessment %K Risk Factors %K Stroke %K Time Factors %K Transforming Growth Factor beta %K United States %X

BACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.

METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β's pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).

CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

%B Circ Arrhythm Electrophysiol %V 7 %P 583-9 %8 2014 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24963008?dopt=Abstract %R 10.1161/CIRCEP.114.001610 %0 Journal Article %J Am J Epidemiol %D 2014 %T Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study. %A Agarwal, Isha %A Glazer, Nicole L %A Barasch, Eddy %A Biggs, Mary L %A Djoussé, Luc %A Fitzpatrick, Annette L %A Gottdiener, John S %A Ix, Joachim H %A Kizer, Jorge R %A Rimm, Eric B %A Siscovick, David S %A Tracy, Russell P %A Zieman, Susan J %A Mukamal, Kenneth J %K Aged %K Aged, 80 and over %K Biomarkers %K Cause of Death %K Female %K Fibrosis %K Follow-Up Studies %K Humans %K Likelihood Functions %K Male %K Multivariate Analysis %K Peptide Fragments %K Procollagen %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Transforming Growth Factor beta %X

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

%B Am J Epidemiol %V 179 %P 1331-9 %8 2014 Jun 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24771724?dopt=Abstract %R 10.1093/aje/kwu067 %0 Journal Article %J J Diabetes Complications %D 2014 %T The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults. %A Vimalananda, Varsha G %A Biggs, Mary L %A Rosenzweig, James L %A Carnethon, Mercedes R %A Meigs, James B %A Thacker, Evan L %A Siscovick, David S %A Mukamal, Kenneth J %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Cohort Studies %K Coronary Disease %K Diabetes Complications %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Incidence %K Longitudinal Studies %K Male %K Prospective Studies %K Regression Analysis %K Retrospective Studies %K Risk Factors %K Sex Factors %K Survival Rate %X

AIMS: It is unknown whether sex differences in the association of diabetes with cardiovascular outcomes vary by race. We examined sex differences in the associations of diabetes with incident congestive heart failure (CHF) and coronary heart disease (CHD) between older black and white adults.

METHODS: We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort study of community-dwelling individuals aged ≥65 from four US counties. We included 4817 participants (476 black women, 279 black men, 2447 white women and 1625 white men). We estimated event rates and multivariate-adjusted hazard ratios for incident CHF, CHD, and all-cause mortality by Cox regression and competing risk analyses.

RESULTS: Over a median follow-up of 12.5years, diabetes was more strongly associated with CHF among black women (HR, 2.42 [95% CI, 1.70-3.40]) than black men (1.39 [0.83-2.34]); this finding did not reach statistical significance (P for interaction=0.08). Female sex conferred a higher risk for a composite outcome of CHF and CHD among black participants (2.44 [1.82-3.26]) vs. (1.44 [0.97-2.12]), P for interaction=0.03). There were no significant sex differences in the HRs associated with diabetes for CHF among whites, or for CHD or all-cause mortality among blacks or whites. The three-way interaction between sex, race, and diabetes on risk of cardiovascular outcomes was not significant (P=0.07).

CONCLUSIONS: Overall, sex did not modify the cardiovascular risk associated with diabetes among older black or white adults. However, our results suggest that a possible sex interaction among older blacks merits further study.

%B J Diabetes Complications %V 28 %P 316-22 %8 2014 May-Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24461547?dopt=Abstract %R 10.1016/j.jdiacomp.2013.12.004 %0 Journal Article %J Hypertension %D 2014 %T Metabolic syndrome and risk of incident peripheral artery disease: the cardiovascular health study. %A Garg, Parveen K %A Biggs, Mary L %A Carnethon, Mercedes %A Ix, Joachim H %A Criqui, Michael H %A Britton, Kathryn A %A Djoussé, Luc %A Sutton-Tyrrell, Kim %A Newman, Anne B %A Cushman, Mary %A Mukamal, Kenneth J %K Aged %K Ankle Brachial Index %K C-Reactive Protein %K Female %K Fibrinogen %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Metabolic Syndrome %K Peripheral Arterial Disease %K Prevalence %K Risk Factors %K Vasculitis %X

Prior studies evaluating metabolic syndrome (MetS) and incident peripheral artery disease (PAD) have been limited by use of modified MetS criteria and restriction to clinical PAD end points. We investigated MetS and risk of developing a low ankle-brachial index (ABI) and clinical PAD in the Cardiovascular Health Study, a population-based cohort of adults aged ≥65 years. Participants with MetS met at least 3 of 5 Adult Treatment Panel III criteria. Baseline C-reactive protein-MetS or fibrinogen-MetS were defined as presence of 3 of 6 components, with elevated C-reactive protein (>3 mg/L) or fibrinogen (>341 mg/dL) as a sixth component. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among a subset of 1899 individuals with 2 ABI measurements 6 years apart. Over a median follow-up of 13.7 years, 4632 individuals were followed up for clinical PAD, defined as revascularization or diagnosed claudication. Adult Treatment Panel III MetS was associated with both incident low ABI (risk ratio, 1.26; 95% confidence interval [CI], 1.00-1.58) and clinical PAD (hazard ratio, 1.47; 95% CI, 1.11-1.94). Incorporating C-reactive protein or fibrinogen into Adult Treatment Panel III criteria identified an additional 16% to 20% of individuals as having MetS, and both C-reactive protein-MetS and fibrinogen-MetS were associated with incident low ABI (risk ratio, 1.36; 95% CI, 1.07-1.72 and risk ratio, 1.43; 95% CI, 1.13-1.81, respectively) and clinical PAD (hazard ratio, 1.56; 95% CI, 1.17-2.08 and hazard ratio, 1.55; 95% CI, 1.17-2.07, respectively). Among Adult Treatment Panel III MetS criteria, risk of PAD was most strongly associated with hypertension.

%B Hypertension %V 63 %P 413-9 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24191289?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.113.01925 %0 Journal Article %J Int J Stroke %D 2014 %T Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study. %A Khawaja, Owais %A Maziarz, Marlena %A Biggs, Mary L %A Longstreth, William T %A Ix, Joachim H %A Kizer, Jorge R %A Zieman, Susan %A Tracy, Russell P %A Mozaffarian, Dariush %A Mukamal, Kenneth J %A Siscovick, David S %A Djoussé, Luc %K Aged %K Biomarkers %K Brain Ischemia %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Male %K Prospective Studies %K Risk %K Stroke %X

BACKGROUND: Although free fatty acids have been positively associated with risk factors for stroke, the role of plasma free fatty acids in the development of stroke has not been elucidated in older adults.

AIMS: We sought to examine the association between plasma free fatty acids and incident stroke.

METHODS: Prospective cohort of 4369 men and women≥65 years of age in the Cardiovascular Health Study. Plasma levels of free fatty acids were measured at the 1992-1993 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with free fatty acids concentrations.

RESULTS: The average age among participants was 75±5·2 years. During a median follow-up of 11·4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14·5, 14·9, and 17·6 per 1000 person-years across increasing tertiles of plasma free fatty acids. The adjusted hazard ratio (95% confidence interval) for incident stroke was 1·05 (0·97-1·14) per standard deviation increase in plasma free fatty acids. Restriction to ischemic stroke did not alter the results [hazard ratio (95% confidence interval): 1·04 (0·96-1·14) per standard deviation higher free fatty acids], and there was no effect modification by adiposity (P interaction=0·18) or by diabetes (P interaction=0·15).

CONCLUSION: Our data did not show an association of plasma free fatty acids with incident stroke among community dwelling older adults.

%B Int J Stroke %V 9 %P 917-20 %8 2014 Oct %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24447493?dopt=Abstract %R 10.1111/ijs.12216 %0 Journal Article %J Am J Cardiol %D 2014 %T Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study). %A Miedema, Michael D %A Maziarz, Marlena %A Biggs, Mary L %A Zieman, Susan J %A Kizer, Jorge R %A Ix, Joachim H %A Mozaffarian, Dariush %A Tracy, Russell P %A Psaty, Bruce M %A Siscovick, David S %A Mukamal, Kenneth J %A Djoussé, Luc %K Age Distribution %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Cardiovascular Diseases %K Cause of Death %K Fatty Acid-Binding Proteins %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Health Status %K Humans %K Male %K Prognosis %K Prospective Studies %K Risk Assessment %K Risk Factors %K Survival Rate %K Time Factors %K United States %X

Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.

%B Am J Cardiol %V 114 %P 843-8 %8 2014 Sep 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25073566?dopt=Abstract %R 10.1016/j.amjcard.2014.06.012 %0 Journal Article %J Clin Endocrinol (Oxf) %D 2014 %T Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. %A Shores, Molly M %A Arnold, Alice M %A Biggs, Mary L %A Longstreth, W T %A Smith, Nicholas L %A Kizer, Jorge R %A Cappola, Anne R %A Hirsch, Calvin H %A Marck, Brett T %A Matsumoto, Alvin M %K Aged %K Aged, 80 and over %K Brain Ischemia %K Cardiovascular Physiological Phenomena %K Dihydrotestosterone %K Health %K Humans %K Incidence %K Longitudinal Studies %K Male %K Stroke %K Testosterone %X

OBJECTIVE: Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men.

DESIGN: Cohort study.

PARTICIPANTS: Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010.

MEASUREMENTS: Adjudicated ischaemic stroke.

RESULTS: Among 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P = 0·006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75 ng/dl, with greater risk of stroke at DHT levels above 75 ng/dl or below 50 ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0·77 (95% CI, 0·61, 0·98) per standard deviation in analyses adjusted for stroke risk factors.

CONCLUSIONS: Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

%B Clin Endocrinol (Oxf) %V 81 %P 746-53 %8 2014 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24645738?dopt=Abstract %R 10.1111/cen.12452 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. %A Shores, Molly M %A Biggs, Mary L %A Arnold, Alice M %A Smith, Nicholas L %A Longstreth, W T %A Kizer, Jorge R %A Hirsch, Calvin H %A Cappola, Anne R %A Matsumoto, Alvin M %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cause of Death %K Dihydrotestosterone %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mortality %K Residence Characteristics %K Risk Factors %K Testosterone %X

CONTEXT: Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this.

OBJECTIVE: The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality.

DESIGN: In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection.

MAIN OUTCOME: The main outcomes were incident CVD and all-cause mortality.

RESULTS: Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both).

CONCLUSIONS: In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.

%B J Clin Endocrinol Metab %V 99 %P 2061-8 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24628549?dopt=Abstract %R 10.1210/jc.2013-3576 %0 Journal Article %J Diabetes Care %D 2015 %T Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study. %A Wang, Qianyi %A Imamura, Fumiaki %A Ma, Wenjie %A Wang, Molin %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Biggs, Mary L %A Delaney, Joseph A %A Mukamal, Kenneth J %A Djoussé, Luc %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Biomarkers %K Diabetes Mellitus, Type 2 %K Diabetic Angiopathies %K Dietary Fats, Unsaturated %K Epidemiologic Methods %K Female %K Food Habits %K Humans %K Male %K Phospholipids %K Trans Fatty Acids %X

OBJECTIVE: To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.

RESEARCH DESIGN AND METHODS: In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 ± 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.

RESULTS: In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00-1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.

CONCLUSIONS: Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.

%B Diabetes Care %V 38 %P 1099-107 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25784660?dopt=Abstract %R 10.2337/dc14-2101 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study. %A Lemaitre, Rozenn N %A Fretts, Amanda M %A Sitlani, Colleen M %A Biggs, Mary L %A Mukamal, Kenneth %A King, Irena B %A Song, Xiaoling %A Djoussé, Luc %A Siscovick, David S %A McKnight, Barbara %A Sotoodehnia, Nona %A Kizer, Jorge R %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Biomarkers %K Cross-Sectional Studies %K Diabetes Mellitus %K Diet %K Eicosanoic Acids %K Fatty Acids %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Observational Studies as Topic %K Palmitic Acid %K Phospholipids %K Prospective Studies %K Risk Factors %K Triglycerides %X

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47% lower risk of diabetes (95% CI: 23%, 63%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33% (95% CI: 6%, 53%; P-trend: 0.02) and 37% (95% CI: 11%, 55%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

%B Am J Clin Nutr %V 101 %P 1047-54 %8 2015 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25787996?dopt=Abstract %R 10.3945/ajcn.114.101857 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Potassium and glucose measures in older adults: the Cardiovascular Health Study. %A Chatterjee, Ranee %A Biggs, Mary L %A de Boer, Ian H %A Brancati, Frederick L %A Svetkey, Laura P %A Barzilay, Joshua %A Djoussé, Luc %A Ix, Joachim H %A Kizer, Jorge R %A Siscovick, David S %A Mozaffarian, Dariush %A Edelman, David %A Mukamal, Kenneth J %K Aged %K Blood Glucose %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Humans %K Insulin %K Insulin Resistance %K Longitudinal Studies %K Male %K Multivariate Analysis %K Potassium %K Potassium, Dietary %K Risk Factors %K United States %X

BACKGROUND: We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.

METHODS: Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.

RESULTS: Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of -0.18 (-0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of -0.61 (-0.94, -0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.

CONCLUSIONS: Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 255-61 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24895271?dopt=Abstract %R 10.1093/gerona/glu071 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. %A Ma, Wenjie %A Wu, Jason H Y %A Wang, Qianyi %A Lemaitre, Rozenn N %A Mukamal, Kenneth J %A Djoussé, Luc %A King, Irena B %A Song, Xiaoling %A Biggs, Mary L %A Delaney, Joseph A %A Kizer, Jorge R %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Biomarkers %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Incidence %K Lipogenesis %K Liver %K Male %K Palmitic Acid %K Phospholipids %K Prevalence %K Proportional Hazards Models %K Risk Factors %K Stearic Acids %K United States %K Up-Regulation %X

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

%B Am J Clin Nutr %V 101 %P 153-63 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25527759?dopt=Abstract %R 10.3945/ajcn.114.092601 %0 Journal Article %J Kidney Int %D 2015 %T Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. %A Garimella, Pranav S %A Biggs, Mary L %A Katz, Ronit %A Ix, Joachim H %A Bennett, Michael R %A Devarajan, Prasad %A Kestenbaum, Bryan R %A Siscovick, David S %A Jensen, Majken K %A Shlipak, Michael G %A Chaves, Paulo H M %A Sarnak, Mark J %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Cardiovascular Diseases %K Case-Control Studies %K Creatinine %K Disease Progression %K Female %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Incidence %K Kidney Failure, Chronic %K Male %K Proportional Hazards Models %K Uromodulin %X

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

%B Kidney Int %V 88 %P 1126-34 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26154925?dopt=Abstract %R 10.1038/ki.2015.192 %0 Journal Article %J J Am Soc Nephrol %D 2015 %T Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study. %A Ix, Joachim H %A Biggs, Mary L %A Mukamal, Kenneth %A Djoussé, Luc %A Siscovick, David %A Tracy, Russell %A Katz, Ronit %A Delaney, Joseph A %A Chaves, Paulo %A Rifkin, Dena E %A Hughes-Austin, Jan M %A Garimella, Pranav S %A Sarnak, Mark J %A Shlipak, Michael G %A Kizer, Jorge R %K Aged %K Cardiovascular Diseases %K Case-Control Studies %K Disease Progression %K Female %K Heart Failure %K Humans %K Kidney Failure, Chronic %K Male %K Peptide Fragments %K Procollagen %K Prospective Studies %K Renal Insufficiency, Chronic %X

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

%B J Am Soc Nephrol %V 26 %P 2494-503 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25655067?dopt=Abstract %R 10.1681/ASN.2014070696 %0 Journal Article %J Diabetes %D 2016 %T Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. %A Walford, Geoffrey A %A Gustafsson, Stefan %A Rybin, Denis %A Stančáková, Alena %A Chen, Han %A Liu, Ching-Ti %A Hong, Jaeyoung %A Jensen, Richard A %A Rice, Ken %A Morris, Andrew P %A Mägi, Reedik %A Tönjes, Anke %A Prokopenko, Inga %A Kleber, Marcus E %A Delgado, Graciela %A Silbernagel, Günther %A Jackson, Anne U %A Appel, Emil V %A Grarup, Niels %A Lewis, Joshua P %A Montasser, May E %A Landenvall, Claes %A Staiger, Harald %A Luan, Jian'an %A Frayling, Timothy M %A Weedon, Michael N %A Xie, Weijia %A Morcillo, Sonsoles %A Martínez-Larrad, María Teresa %A Biggs, Mary L %A Chen, Yii-Der Ida %A Corbaton-Anchuelo, Arturo %A Færch, Kristine %A Gómez-Zumaquero, Juan Miguel %A Goodarzi, Mark O %A Kizer, Jorge R %A Koistinen, Heikki A %A Leong, Aaron %A Lind, Lars %A Lindgren, Cecilia %A Machicao, Fausto %A Manning, Alisa K %A Martín-Núñez, Gracia María %A Rojo-Martínez, Gemma %A Rotter, Jerome I %A Siscovick, David S %A Zmuda, Joseph M %A Zhang, Zhongyang %A Serrano-Ríos, Manuel %A Smith, Ulf %A Soriguer, Federico %A Hansen, Torben %A Jørgensen, Torben J %A Linnenberg, Allan %A Pedersen, Oluf %A Walker, Mark %A Langenberg, Claudia %A Scott, Robert A %A Wareham, Nicholas J %A Fritsche, Andreas %A Häring, Hans-Ulrich %A Stefan, Norbert %A Groop, Leif %A O'Connell, Jeff R %A Boehnke, Michael %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A März, Winfried %A Kovacs, Peter %A Stumvoll, Michael %A Psaty, Bruce M %A Kuusisto, Johanna %A Laakso, Markku %A Meigs, James B %A Dupuis, Josée %A Ingelsson, Erik %A Florez, Jose C %X

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

%B Diabetes %V 65 %P 3200-11 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract %R 10.2337/db16-0199 %0 Journal Article %J Circulation %D 2016 %T Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. %A Waks, Jonathan W %A Sitlani, Colleen M %A Soliman, Elsayed Z %A Kabir, Muammar %A Ghafoori, Elyar %A Biggs, Mary L %A Henrikson, Charles A %A Sotoodehnia, Nona %A Biering-Sørensen, Tor %A Agarwal, Sunil K %A Siscovick, David S %A Post, Wendy S %A Solomon, Scott D %A Buxton, Alfred E %A Josephson, Mark E %A Tereshchenko, Larisa G %X

BACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.

METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%.

CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

%B Circulation %V 133 %P 2222-34 %8 2016 Jun 7 %G eng %N 23 %R 10.1161/CIRCULATIONAHA.116.021306 %0 Journal Article %J Am J Clin Nutr %D 2016 %T Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Ma, Yiyi %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Manichaikul, Ani W %A Chu, Audrey Y %A Samieri, Cecilia %A Zhou, Xia %A Guan, Weihua %A Wang, Lu %A Biggs, Mary L %A Chen, Yii-der I %A Hernandez, Dena G %A Borecki, Ingrid %A Chasman, Daniel I %A Rich, Stephen S %A Ferrucci, Luigi %A Irvin, Marguerite Ryan %A Aslibekyan, Stella %A Zhi, Degui %A Tiwari, Hemant K %A Claas, Steven A %A Sha, Jin %A Kabagambe, Edmond K %A Lai, Chao-Qiang %A Parnell, Laurence D %A Lee, Yu-Chi %A Amouyel, Philippe %A Lambert, Jean-Charles %A Psaty, Bruce M %A King, Irena B %A Mozaffarian, Dariush %A McKnight, Barbara %A Bandinelli, Stefania %A Tsai, Michael Y %A Ridker, Paul M %A Ding, Jingzhong %A Mstat, Kurt Lohmant %A Liu, Yongmei %A Sotoodehnia, Nona %A Barberger-Gateau, Pascale %A Steffen, Lyn M %A Siscovick, David S %A Absher, Devin %A Arnett, Donna K %A Ordovas, Jose M %A Lemaitre, Rozenn N %K Apolipoproteins E %K ATP Binding Cassette Transporter 1 %K Cholesterol, HDL %K Cohort Studies %K Diet %K DNA Methylation %K Eicosapentaenoic Acid %K Epigenesis, Genetic %K Fatty Acids %K Gene Expression Regulation %K Humans %K Lipids %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Triglycerides %X

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

%B Am J Clin Nutr %V 103 %P 567-78 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract %R 10.3945/ajcn.115.112987 %0 Journal Article %J Metabolism %D 2016 %T Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study. %A Brutsaert, Erika F %A Biggs, Mary L %A Delaney, Joseph A %A Djoussé, Luc %A Gottdiener, John S %A Ix, Joachim H %A Kim, Francis %A Mukamal, Kenneth J %A Siscovick, David S %A Tracy, Russell P %A de Boer, Ian H %A deFilippi, Christopher R %A Kizer, Jorge R %X

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways.

METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study.

RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9% lower risk of incident diabetes (HR=0.91 [95% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP.

CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

%B Metabolism %V 65 %P 1489-97 %8 2016 Oct %G eng %N 10 %R 10.1016/j.metabol.2016.06.002 %0 Journal Article %J Am J Epidemiol %D 2016 %T Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study. %A Karas, Maria G %A Yee, Laura M %A Biggs, Mary L %A Djoussé, Luc %A Mukamal, Kenneth J %A Ix, Joachim H %A Zieman, Susan J %A Siscovick, David S %A Gottdiener, John S %A Rosenberg, Michael A %A Kronmal, Richard A %A Heckbert, Susan R %A Kizer, Jorge R %X

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

%B Am J Epidemiol %V 183 %P 998-1007 %8 2016 Jun 1 %G eng %N 11 %R 10.1093/aje/kwv278 %0 Journal Article %J J Clin Endocrinol Metab %D 2016 %T Testosterone, Dihydrotestosterone, Sex Hormone Binding Globulin and Incident Diabetes among Older Men: the Cardiovascular Health Study. %A Joyce, Katherine E %A Biggs, Mary L %A Djoussé, Luc %A Ix, Joachim H %A Kizer, Jorge R %A Siscovick, David S %A Shores, Molly M %A Matsumoto, Alvin M %A Mukamal, Kenneth J %X

CONTEXT: Although sex hormone binding globulin (SHBG) and testosterone (T) have been inversely associated with risk of diabetes, few studies have examined dihydrotestosterone (DHT), a more potent androgen than T, or older adults, whose glycemic pathophysiology differs from younger adults.

OBJECTIVE: To determine the associations of SHBG, T, and DHT with insulin resistance and incident diabetes in older adult men.

DESIGN: In a prospective cohort study, we evaluated baseline levels of SHBG, T, and DHT using liquid chromatography-tandem mass spectrometry among 852 men in the Cardiovascular Health Study free of diabetes and cardiovascular disease in 1994.

MAIN OUTCOME: Insulin resistance estimated by HOMA-IR and insulin sensitivity estimated by the Gutt index in 1996, and incident diabetes (n=112) ascertained over a mean follow-up of 9.8 years.

RESULTS: In linear regression models adjusted for demographics, alcohol consumption, current smoking, body-mass index, and other androgens, SHBG (HOMA-IR 0.30 units lower per doubling; 95% confidence interval [CI], 0.08-0.52; p=0.01) and total DHT (HOMA-IR 0.18 units lower per doubling; 95% CI 0.06-0.30; p=0.01), but not free T (p=0.33) were inversely associated with insulin resistance. In corresponding Cox proportional hazards models, total DHT was again inversely associated with risk of diabetes (adjusted hazard ratio per doubling 0.69; 95% CI, 0.52-0.92; p=0.01), but SHBG (hazard ratio 1.09; 95% CI, 0.74-1.59; p=0.66) and free T (hazard ratio 1.15; 95% CI, 0.92-1.43; p=0.23) were not.

CONCLUSIONS: Among older men, higher levels of DHT are inversely associated with insulin resistance and risk of diabetes over the ensuing 10 years, while levels of T are not. Future studies are still needed to clarify the role of SHBG in risk of diabetes in this population.

%B J Clin Endocrinol Metab %P jc20162623 %8 2016 Oct 12 %G eng %R 10.1210/jc.2016-2623 %0 Journal Article %J Am J Hum Genet %D 2016 %T Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. %A Liu, Ching-Ti %A Raghavan, Sridharan %A Maruthur, Nisa %A Kabagambe, Edmond Kato %A Hong, Jaeyoung %A Ng, Maggie C Y %A Hivert, Marie-France %A Lu, Yingchang %A An, Ping %A Bentley, Amy R %A Drolet, Anne M %A Gaulton, Kyle J %A Guo, Xiuqing %A Armstrong, Loren L %A Irvin, Marguerite R %A Li, Man %A Lipovich, Leonard %A Rybin, Denis V %A Taylor, Kent D %A Agyemang, Charles %A Palmer, Nicholette D %A Cade, Brian E %A Chen, Wei-Min %A Dauriz, Marco %A Delaney, Joseph A C %A Edwards, Todd L %A Evans, Daniel S %A Evans, Michele K %A Lange, Leslie A %A Leong, Aaron %A Liu, Jingmin %A Liu, Yongmei %A Nayak, Uma %A Patel, Sanjay R %A Porneala, Bianca C %A Rasmussen-Torvik, Laura J %A Snijder, Marieke B %A Stallings, Sarah C %A Tanaka, Toshiko %A Yanek, Lisa R %A Zhao, Wei %A Becker, Diane M %A Bielak, Lawrence F %A Biggs, Mary L %A Bottinger, Erwin P %A Bowden, Donald W %A Chen, Guanjie %A Correa, Adolfo %A Couper, David J %A Crawford, Dana C %A Cushman, Mary %A Eicher, John D %A Fornage, Myriam %A Franceschini, Nora %A Fu, Yi-Ping %A Goodarzi, Mark O %A Gottesman, Omri %A Hara, Kazuo %A Harris, Tamara B %A Jensen, Richard A %A Johnson, Andrew D %A Jhun, Min A %A Karter, Andrew J %A Keller, Margaux F %A Kho, Abel N %A Kizer, Jorge R %A Krauss, Ronald M %A Langefeld, Carl D %A Li, Xiaohui %A Liang, Jingling %A Liu, Simin %A Lowe, William L %A Mosley, Thomas H %A North, Kari E %A Pacheco, Jennifer A %A Peyser, Patricia A %A Patrick, Alan L %A Rice, Kenneth M %A Selvin, Elizabeth %A Sims, Mario %A Smith, Jennifer A %A Tajuddin, Salman M %A Vaidya, Dhananjay %A Wren, Mary P %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Julie T %A Zmuda, Joseph M %A Zonderman, Alan B %A Zwinderman, Aeilko H %A Adeyemo, Adebowale %A Boerwinkle, Eric %A Ferrucci, Luigi %A Hayes, M Geoffrey %A Kardia, Sharon L R %A Miljkovic, Iva %A Pankow, James S %A Rotimi, Charles N %A Sale, Michèle M %A Wagenknecht, Lynne E %A Arnett, Donna K %A Chen, Yii-Der Ida %A Nalls, Michael A %A Province, Michael A %A Kao, W H Linda %A Siscovick, David S %A Psaty, Bruce M %A Wilson, James G %A Loos, Ruth J F %A Dupuis, Josée %A Rich, Stephen S %A Florez, Jose C %A Rotter, Jerome I %A Morris, Andrew P %A Meigs, James B %X

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

%B Am J Hum Genet %V 99 %P 56-75 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract %R 10.1016/j.ajhg.2016.05.006 %0 Journal Article %J J Clin Endocrinol Metab %D 2017 %T The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study. %A Aneke-Nash, Chino S %A Xue, XiaoNan %A Qi, Qibin %A Biggs, Mary L %A Cappola, Anne %A Kuller, Lewis %A Pollak, Michael %A Psaty, Bruce M %A Siscovick, David %A Mukamal, Kenneth %A Strickler, Howard D %A Kaplan, Robert C %K Aged %K Aged, 80 and over %K Biomarkers %K Blood Glucose %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Mellitus %K Female %K Humans %K Incidence %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Longitudinal Studies %K Male %K New England %K Prospective Studies %K Risk %X

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

%B J Clin Endocrinol Metab %V 102 %P 4541-4547 %8 2017 Dec 01 %G eng %N 12 %R 10.1210/jc.2017-01273 %0 Journal Article %J Am J Epidemiol %D 2017 %T Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults. %A Greenlee, Heather %A Strizich, Garrett %A Lovasi, Gina S %A Kaplan, Robert C %A Biggs, Mary L %A Li, Christopher I %A Richardson, John %A Burke, Gregory L %A Fitzpatrick, Annette L %A Fretts, Amanda M %A Psaty, Bruce M %A Fried, Linda P %K Aged %K Aged, 80 and over %K American Cancer Society %K American Heart Association %K Body Mass Index %K Cardiovascular Diseases %K Cause of Death %K Diet %K Exercise %K Female %K Guideline Adherence %K Healthy Lifestyle %K Humans %K Incidence %K Longitudinal Studies %K Male %K Neoplasms %K Practice Guidelines as Topic %K Prospective Studies %K United States %X

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

%B Am J Epidemiol %V 186 %P 1168-1179 %8 2017 Nov 15 %G eng %N 10 %R 10.1093/aje/kwx150 %0 Journal Article %J Am J Hum Genet %D 2017 %T Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. %A Manousaki, Despoina %A Dudding, Tom %A Haworth, Simon %A Hsu, Yi-Hsiang %A Liu, Ching-Ti %A Medina-Gómez, Carolina %A Voortman, Trudy %A van der Velde, Nathalie %A Melhus, Håkan %A Robinson-Cohen, Cassianne %A Cousminer, Diana L %A Nethander, Maria %A Vandenput, Liesbeth %A Noordam, Raymond %A Forgetta, Vincenzo %A Greenwood, Celia M T %A Biggs, Mary L %A Psaty, Bruce M %A Rotter, Jerome I %A Zemel, Babette S %A Mitchell, Jonathan A %A Taylor, Bruce %A Lorentzon, Mattias %A Karlsson, Magnus %A Jaddoe, Vincent V W %A Tiemeier, Henning %A Campos-Obando, Natalia %A Franco, Oscar H %A Utterlinden, Andre G %A Broer, Linda %A van Schoor, Natasja M %A Ham, Annelies C %A Ikram, M Arfan %A Karasik, David %A de Mutsert, Renée %A Rosendaal, Frits R %A den Heijer, Martin %A Wang, Thomas J %A Lind, Lars %A Orwoll, Eric S %A Mook-Kanamori, Dennis O %A Michaëlsson, Karl %A Kestenbaum, Bryan %A Ohlsson, Claes %A Mellström, Dan %A de Groot, Lisette C P G M %A Grant, Struan F A %A Kiel, Douglas P %A Zillikens, M Carola %A Rivadeneira, Fernando %A Sawcer, Stephen %A Timpson, Nicholas J %A Richards, J Brent %K Cholestanetriol 26-Monooxygenase %K Cytochrome P450 Family 2 %K Gene Frequency %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Multiple Sclerosis %K Polymorphism, Single Nucleotide %K Risk Factors %K Vitamin D %K Vitamin D Deficiency %X

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

%B Am J Hum Genet %V 101 %P 227-238 %8 2017 Aug 03 %G eng %N 2 %R 10.1016/j.ajhg.2017.06.014 %0 Journal Article %J Diabetes Care %D 2018 %T Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study. %A Massera, Daniele %A Biggs, Mary L %A Walker, Marcella D %A Mukamal, Kenneth J %A Ix, Joachim H %A Djoussé, Luc %A Valderrábano, Rodrigo J %A Siscovick, David S %A Tracy, Russell P %A Xue, XiaoNan %A Kizer, Jorge R %X

OBJECTIVE: To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women.

RESEARCH DESIGN AND METHODS: The analysis included 1,455 female participants from the population-based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models.

RESULTS: OC and CTX were strongly correlated ( = 0.80). In cross-sectional analyses, significant or near-significant inverse associations with HOMA-IR were observed for continuous levels of OC (β = -0.12 per SD increment; = 0.004) and CTX (β = -0.08 per SD; = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95% CI 0.71-1.02; = 0.075]; CTX: 0.82 per SD [0.69-0.98; = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance.

CONCLUSIONS: In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

%B Diabetes Care %V 41 %P 1901-1908 %8 2018 09 %G eng %N 9 %R 10.2337/dc18-0849 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study). %A Tereshchenko, Larisa G %A Sotoodehnia, Nona %A Sitlani, Colleen M %A Ashar, Foram N %A Kabir, Muammar %A Biggs, Mary L %A Morley, Michael P %A Waks, Jonathan W %A Soliman, Elsayed Z %A Buxton, Alfred E %A Biering-Sørensen, Tor %A Solomon, Scott D %A Post, Wendy S %A Cappola, Thomas P %A Siscovick, David S %A Arking, Dan E %X

BACKGROUND: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.

METHODS AND RESULTS: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; =1.5×10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1×10), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; =5.9×10). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).

CONCLUSIONS: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

%B J Am Heart Assoc %V 7 %8 2018 Apr 05 %G eng %N 8 %R 10.1161/JAHA.117.008160 %0 Journal Article %J Diab Vasc Dis Res %D 2019 %T Advanced glycation end product carboxymethyl-lysine and risk of incident peripheral artery disease in older adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Biggs, Mary L %A Barzilay, Joshua %A Djoussé, Luc %A Hirsch, Calvin %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell P %A Newman, Anne B %A Siscovick, David S %A Mukamal, Kenneth J %X

Carboxymethyl-lysine is an advanced glycation end product that is detectable in the serum. Higher carboxymethyl-lysine levels have been associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. We determined whether high carboxymethyl-lysine levels are also associated with the risk of peripheral artery disease in Cardiovascular Health Study participants who were all aged 65 years and older at baseline. Multivariate Cox proportional hazards models were used to determine the association of baseline carboxymethyl-lysine levels with incident peripheral artery disease in 3267 individuals followed for a median length of 10.0 years. A total of 157 cases of incident peripheral artery disease occurred during follow-up. No significant relationship between carboxymethyl-lysine and risk of peripheral artery disease was found (hazard ratio per standard deviation increment = 1.03; 95% confidence interval = 0.87, 1.23).

%B Diab Vasc Dis Res %P 1479164119847481 %8 2019 May 08 %G eng %R 10.1177/1479164119847481 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Nat Genet %D 2019 %T Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. %A Tin, Adrienne %A Marten, Jonathan %A Halperin Kuhns, Victoria L %A Li, Yong %A Wuttke, Matthias %A Kirsten, Holger %A Sieber, Karsten B %A Qiu, Chengxiang %A Gorski, Mathias %A Yu, Zhi %A Giri, Ayush %A Sveinbjornsson, Gardar %A Li, Man %A Chu, Audrey Y %A Hoppmann, Anselm %A O'Connor, Luke J %A Prins, Bram %A Nutile, Teresa %A Noce, Damia %A Akiyama, Masato %A Cocca, Massimiliano %A Ghasemi, Sahar %A van der Most, Peter J %A Horn, Katrin %A Xu, Yizhe %A Fuchsberger, Christian %A Sedaghat, Sanaz %A Afaq, Saima %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boerwinkle, Eric %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brumat, Marco %A Burkhardt, Ralph %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Ciullo, Marina %A Concas, Maria Pina %A Coresh, Josef %A Corre, Tanguy %A Cusi, Daniele %A Felicita, Sala Cinzia %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Delgado, Graciela %A Demirkan, Ayse %A Devuyst, Olivier %A Dittrich, Katalin %A Eckardt, Kai-Uwe %A Ehret, Georg %A Endlich, Karlhans %A Evans, Michele K %A Gansevoort, Ron T %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hayward, Caroline %A Hicks, Andrew A %A Hofer, Edith %A Holm, Hilma %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Lewis, Raychel M %A Ingelsson, Erik %A Jakobsdottir, Johanna %A Jonsdottir, Ingileif %A Jonsson, Helgi %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerr, Shona M %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A La Bianca, Martina %A Lange, Leslie A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liu, Jun %A Loeffler, Markus %A Loos, Ruth J F %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mahajan, Anubha %A Martin, Nicholas G %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A O'Donnell, Christopher J %A Wilson, Otis D %A Gaziano, J Michael %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Müller-Nurasyid, Martina %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey R %A Olafsson, Isleifur %A Padmanabhan, Sandosh %A Penninx, Brenda W J H %A Perls, Thomas %A Peters, Annette %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Preuss, Michael H %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Robino, Antonietta %A Rudan, Igor %A Krajcoviechova, Alena %A Cifkova, Renata %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Shaffer, Christian M %A Smith, Albert V %A Smith, Blair H %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stumvoll, Michael %A Sulem, Patrick %A Tajuddin, Salman M %A Teren, Andrej %A Thiery, Joachim %A Thio, Chris H L %A Thorsteinsdottir, Unnur %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Uitterlinden, André G %A Vaccargiu, Simona %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Yang, Qiong %A Zhang, Weihua %A Zonderman, Alan B %A Bochud, Murielle %A Wilson, James G %A Pendergrass, Sarah A %A Ho, Kevin %A Parsa, Afshin %A Pramstaller, Peter P %A Psaty, Bruce M %A Böger, Carsten A %A Snieder, Harold %A Butterworth, Adam S %A Okada, Yukinori %A Edwards, Todd L %A Stefansson, Kari %A Susztak, Katalin %A Scholz, Markus %A Heid, Iris M %A Hung, Adriana M %A Teumer, Alexander %A Pattaro, Cristian %A Woodward, Owen M %A Vitart, Veronique %A Köttgen, Anna %X

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

%B Nat Genet %V 51 %P 1459-1474 %8 2019 Oct %G eng %N 10 %R 10.1038/s41588-019-0504-x %0 Journal Article %J J Am Heart Assoc %D 2020 %T Fatty Acid Binding Protein-4 and Risk of Cardiovascular Disease: The Cardiovascular Health Study. %A Egbuche, Obiora %A Biggs, Mary L %A Ix, Joachim H %A Kizer, Jorge R %A Lyles, Mary F %A Siscovick, David S %A Djoussé, Luc %A Mukamal, Kenneth J %X

Background FABP-4 (fatty acid binding protein-4) is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP-4, risk of incident cardiovascular disease (CVD), and risk of CVD mortality among older adults with and without established CVD. Methods and Results In the Cardiovascular Health Study, we measured FABP4 levels in stored specimens from the 1992-993 visit and followed participants for incident CVD if they were free of prevalent CVD at baseline and for CVD mortality through June 2015. We used Cox regression to estimate hazard ratios for incident CVD and CVD mortality per doubling in serum FABP-4 adjusted for age, sex, race, field center, waist circumference, blood pressure, lipids, fasting glucose, and C-reactive protein. Among 4026 participants free of CVD and 681 with prevalent CVD, we documented 1878 cases of incident CVD and 331 CVD deaths, respectively. In adjusted analyses, FABP-4 was modestly associated with risk of incident CVD (mean, 34.24; SD, 18.90; HR, 1.10 per doubling in FABP-4, 95% CI, 1.00-1.21). In contrast, FABP-4 was more clearly associated with risk of CVD mortality among participants without (HR hazard ratio 1.24, 95% CI, 1.10-1.40) or with prevalent CVD (HR hazard ratio 1.57, 95% CI, 1.24-1.98). These associations were not significantly modified by sex, age, and waist circumference. Conclusions Serum FABP-4 is modestly associated with risk of incident CVD even after adjustment for standard risk factors, but more strongly associated with CVD mortality among older adults with and without established CVD.

%B J Am Heart Assoc %V 9 %P e014070 %8 2020 Apr 07 %G eng %N 7 %R 10.1161/JAHA.119.014070 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2020 %T Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90. %A Häberle, Astrid D %A Biggs, Mary L %A Cushman, Mary %A Psaty, Bruce M %A Newman, Anne B %A Shlipak, Michael G %A Gottdiener, John %A Wu, Chenkai %A Gardin, Julius M %A Bansal, Nisha %A Odden, Michelle C %X

BACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.

METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.

RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90.

CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

%B J Gerontol A Biol Sci Med Sci %8 2020 May 17 %G eng %R 10.1093/gerona/glaa124 %0 Journal Article %J Kidney Int %D 2020 %T Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. %A Gorski, Mathias %A Jung, Bettina %A Li, Yong %A Matias-Garcia, Pamela R %A Wuttke, Matthias %A Coassin, Stefan %A Thio, Chris H L %A Kleber, Marcus E %A Winkler, Thomas W %A Wanner, Veronika %A Chai, Jin-Fang %A Chu, Audrey Y %A Cocca, Massimiliano %A Feitosa, Mary F %A Ghasemi, Sahar %A Hoppmann, Anselm %A Horn, Katrin %A Li, Man %A Nutile, Teresa %A Scholz, Markus %A Sieber, Karsten B %A Teumer, Alexander %A Tin, Adrienne %A Wang, Judy %A Tayo, Bamidele O %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Carroll, Robert J %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Coresh, Josef %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Franke, Andre %A Freitag-Wolf, Sandra %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Gieger, Christian %A Hamet, Pavel %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Xian Foo, Valencia Hui %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Kähönen, Mika %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Lange, Leslie A %A Lehtimäki, Terho %A Lieb, Wolfgang %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A O'Donoghue, Michelle L %A Orho-Melander, Marju %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Sabanayagam, Charumathi %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Strauch, Konstantin %A Szymczak, Silke %A Taylor, Kent D %A Tremblay, Johanne %A Chaker, Layal %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Waldenberger, Melanie %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Yan %A Snieder, Harold %A Wanner, Christoph %A Böger, Carsten A %A Köttgen, Anna %A Kronenberg, Florian %A Pattaro, Cristian %A Heid, Iris M %X

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

%B Kidney Int %8 2020 Oct 30 %G eng %R 10.1016/j.kint.2020.09.030 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2020 %T Patterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90. %A Odden, Michelle C %A Rawlings, Andreea M %A Arnold, Alice M %A Cushman, Mary %A Biggs, Mary L %A Psaty, Bruce M %A Newman, Anne B %X

BACKGROUND: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age.

METHODS: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15-23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67-75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years).

RESULTS: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants' 80's. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability.

CONCLUSION: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes.

%B J Gerontol A Biol Sci Med Sci %8 2020 Apr 08 %G eng %R 10.1093/gerona/glaa043 %0 Journal Article %J JAMA Netw Open %D 2021 %T Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging. %A Bockus, Lee B %A Biggs, Mary L %A Lai, Heidi T M %A de Olivera Otto, Marcia C %A Fretts, Amanda M %A McKnight, Barbara %A Sotoodehnia, Nona %A King, Irena B %A Song, Xiaoling %A Siscovick, David S %A Mozaffarian, Dariush %A Lemaitre, Rozenn N %X

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown.

Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline.

Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020.

Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid.

Results: Among the 2680 study participants (976 men [36.4%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15% lower risk of an unhealthy event (HR, 0.85; 95% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16% lower risk of an unhealthy event (HR, 0.84; 95% CI, 0.73-0.95; P for trend = .001).

Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

%B JAMA Netw Open %V 4 %P e2120616 %8 2021 Aug 02 %G eng %N 8 %R 10.1001/jamanetworkopen.2021.20616 %0 Journal Article %J JAMA Netw Open %D 2021 %T Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study. %A Lemaitre, Rozenn N %A Jensen, Paul N %A Wang, Zeneng %A Fretts, Amanda M %A McKnight, Barbara %A Nemet, Ina %A Biggs, Mary L %A Sotoodehnia, Nona %A de Oliveira Otto, Marcia C %A Psaty, Bruce M %A Siscovick, David S %A Hazen, Stanley L %A Mozaffarian, Dariush %X

Importance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.

Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).

Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.

Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.

Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.

Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine).

Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.

%B JAMA Netw Open %V 4 %P e2122844 %8 2021 Aug 02 %G eng %N 8 %R 10.1001/jamanetworkopen.2021.22844 %0 Journal Article %J Soc Psychiatry Psychiatr Epidemiol %D 2021 %T Associations between neighborhood greenspace and brain imaging measures in non-demented older adults: the Cardiovascular Health Study. %A Besser, Lilah M %A Lovasi, Gina S %A Michael, Yvonne L %A Garg, Parveen %A Hirsch, Jana A %A Siscovick, David %A Hurvitz, Phil %A Biggs, Mary L %A Galvin, James E %A Bartz, Traci M %A Longstreth, W T %X

PURPOSE: Greater neighborhood greenspace has been associated with brain health, including better cognition and lower odds of Alzheimer's disease in older adults. We investigated associations between neighborhood greenspace and brain-based magnetic resonance imaging (MRI) measures and potential effect modification by sex or apolipoprotein E genotype (APOE), a risk factor for Alzheimer's disease.

METHODS: We obtained a sample of non-demented participants 65 years or older (n = 1125) from the longitudinal, population-based Cardiovascular Health Study (CHS). Greenspace data were derived from the National Land Cover Dataset. Adjusted multivariable linear regression estimated associations between neighborhood greenspace five years prior to the MRI and left and right hippocampal volume and 10-point grades of ventricular size and burden of white matter hyperintensity. Interaction terms tested effect modification by APOE genotype and sex. CHS data (1989-1999) were obtained/analyzed in 2020.

RESULTS: Participants were on average 79 years old [standard deviation (SD) = 4], 58% were female, and 11% were non-white race. Mean neighborhood greenspace was 38% (SD = 28%). Greater proportion of greenspace in the neighborhood five years before MRI was borderline associated with lower ventricle grade (estimate: - 0.30; 95% confidence interval: - 0.61, 0.00). We observed no associations between greenspace and the other MRI outcome measures and no evidence of effect modification by APOE genotype and sex.

CONCLUSION: This study suggests a possible association between greater greenspace and less ventricular enlargement, a measure reflecting global brain atrophy. If confirmed in other longitudinal cohort studies, interventions and policies to improve community greenspaces may help to maintain brain health in older age.

%B Soc Psychiatry Psychiatr Epidemiol %8 2021 Jan 03 %G eng %R 10.1007/s00127-020-02000-w %0 Journal Article %J J Clin Endocrinol Metab %D 2021 %T Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes. %A Nair, Nandini %A Vittinghoff, Eric %A Pletcher, Mark J %A Oelsner, Elizabeth C %A Allen, Norrina B %A Ndumele, Chiadi E %A West, Nancy A %A Strotmeyer, Elsa S %A Mukamal, Kenneth J %A Siscovick, David S %A Biggs, Mary L %A Laferrère, Blandine %A Moran, Andrew E %A Zhang, Yiyi %K Adolescent %K Adult %K Biomarkers %K Body Mass Index %K Diabetes Mellitus %K Female %K Follow-Up Studies %K Humans %K Male %K Obesity %K Overweight %K Prognosis %K Prospective Studies %K Risk Factors %K United States %K Waist Circumference %K Young Adult %X

CONTEXT: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.

OBJECTIVE: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years).

DESIGN: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.

SETTING: Population-based cohort studies.

PARTICIPANTS: 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40.

INTERVENTIONS: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.

MAIN OUTCOME MEASURE(S): Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications.

RESULTS: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.

CONCLUSIONS: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.

%B J Clin Endocrinol Metab %V 106 %P e5011-e5020 %8 2021 11 19 %G eng %N 12 %R 10.1210/clinem/dgab551 %0 Journal Article %J Heart %D 2021 %T Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults. %A Owens, David S %A Bartz, Traci M %A Bůzková, Petra %A Massera, Daniele %A Biggs, Mary L %A Carlson, Selma D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Gottdiener, John S %A Kizer, Jorge R %X

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

%B Heart %8 2021 Jun 02 %G eng %R 10.1136/heartjnl-2021-319025 %0 Journal Article %J Clin Nutr %D 2021 %T Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts. %A Djoussé, Luc %A Zhou, Guohai %A McClelland, Robyn L %A Ma, Nanxun %A Zhou, Xia %A Kabagambe, Edmond K %A Talegawkar, Sameera A %A Judd, Suzanne E %A Biggs, Mary L %A Fitzpatrick, Annette L %A Clark, Cheryl R %A Gagnon, David R %A Steffen, Lyn M %A Gaziano, J Michael %A Lee, I-Min %A Buring, Julie E %A Manson, JoAnn E %K Adult %K Aged %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Diet %K Eggs %K Humans %K Middle Aged %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults.

DESIGN: We used prospective cohort design to complete time-to-event analyses.

METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks.

RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week.

CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

%B Clin Nutr %V 40 %P 2475-2482 %8 2021 05 %G eng %N 5 %R 10.1016/j.clnu.2021.03.003 %0 Journal Article %J PLoS One %D 2021 %T Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program. %A Sarnowski, Chloe %A Chen, Han %A Biggs, Mary L %A Wassertheil-Smoller, Sylvia %A Bressler, Jan %A Irvin, Marguerite R %A Ryan, Kathleen A %A Karasik, David %A Arnett, Donna K %A Cupples, L Adrienne %A Fardo, David W %A Gogarten, Stephanie M %A Heavner, Benjamin D %A Jain, Deepti %A Kang, Hyun Min %A Kooperberg, Charles %A Mainous, Arch G %A Mitchell, Braxton D %A Morrison, Alanna C %A O'Connell, Jeffrey R %A Psaty, Bruce M %A Rice, Kenneth %A Smith, Albert V %A Vasan, Ramachandran S %A Windham, B Gwen %A Kiel, Douglas P %A Murabito, Joanne M %A Lunetta, Kathryn L %X

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

%B PLoS One %V 16 %P e0253611 %8 2021 %G eng %N 7 %R 10.1371/journal.pone.0253611 %0 Journal Article %J Am J Kidney Dis %D 2021 %T Nonesterified Fatty Acids and Kidney Function Decline in Older Adults: Findings From the Cardiovascular Health Study. %A Walther, Carl P %A Ix, Joachim H %A Biggs, Mary L %A Kizer, Jorge R %A Navaneethan, Sankar D %A Djoussé, Luc %A Mukamal, Kenneth J %X

RATIONALE & OBJECTIVE: Circulating non-esterified fatty acids (NEFAs) make up a small portion of circulating lipids but are a metabolically important energy source. Excessive circulating NEFAs may contribute to lipotoxicity in many tissues, including the kidneys. We investigated the relationship between total circulating NEFA concentration and kidney outcomes in older, community-dwelling adults.

STUDY DESIGN: Prospective cohort study.

SETTING & PARTICIPANTS: 4,698 participants ≥65 years of age in the Cardiovascular Health Study who underwent total fasting serum NEFA concentration measurements in 1992-1993.

EXPOSURE: Fasting serum NEFA concentration at one timepoint.

OUTCOMES: Three primary outcomes: estimated glomerular filtration rate (eGFR) decline of >30%; the composite of eGFR decline ≥30% or kidney failure with replacement therapy (KFRT); and change in eGFR. These outcomes were assessed over 4- and 13-year periods.

ANALYTICAL APPROACH: Logistic regression for the dichotomous outcomes and mixed effects models for the continuous outcome, with sequential adjustment for baseline covariates. Inverse probability of attrition weighting was implemented to account for informative attrition during the follow-up periods.

RESULTS: Serum NEFA concentrations were not independently associated with kidney outcomes. In unadjusted and partially adjusted analyses, the highest quartile of serum NEFA concentration (compared to lowest) was associated with a higher risk of ≥30% eGFR decline at 4 years and faster rate of decline of eGFR. No associations were evident after adjustment for comorbidities, lipid levels, insulin sensitivity, medications, and vital signs: odds ratio 1.33 (95%CI 0.83-2.13); estimated glomerular filtration rate change per year, Q4 vs Q1: -0.15 ml/min/1.73m/year (95%CI -0.36 to 0.06).

LIMITATIONS: Single NEFA measurements, no measurements of post-glucose load NEFA concentrations or individual NEFA species, no measurement of baseline urine albumin.

CONCLUSIONS: A single fasting serum NEFA concentration was not independently associated with long-term adverse kidney outcomes in a cohort of older community-living adults.

%B Am J Kidney Dis %8 2021 Feb 03 %G eng %R 10.1053/j.ajkd.2020.11.030 %0 Journal Article %J Cardiology %D 2021 %T Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults. %A Djoussé, Luc %A Biggs, Mary L %A Matthan, Nirupa R %A Ix, Joachim H %A Fitzpatrick, Annette L %A King, Irena %A Lemaitre, Rozenn N %A McKnight, Barbara %A Kizer, Jorge R %A Lichtenstein, Alice H %A Mukamal, Kenneth J %A Siscovick, David S %X

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 ± 4.4 years, and 38.8% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

%B Cardiology %P 1-8 %8 2021 Feb 25 %G eng %R 10.1159/000513917 %0 Journal Article %J J Am Heart Assoc %D 2021 %T Serum Nonesterified Fatty Acids and Incident Stroke: The CHS. %A Huang, Neil K %A Biggs, Mary L %A Matthan, Nirupa R %A Djoussé, Luc %A Longstreth, W T %A Mukamal, Kenneth J %A Siscovick, David S %A Lichtenstein, Alice H %K 8,11,14-Eicosatrienoic Acid %K Fatty Acids, Nonesterified %K Fatty Acids, Omega-3 %K Hemorrhagic Stroke %K Humans %K Prospective Studies %K Risk Factors %K Stroke %K Trans Fatty Acids %X

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas -7-hexadecenoic acid (16:1n-9) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

%B J Am Heart Assoc %V 10 %P e022725 %8 2021 11 16 %G eng %N 22 %R 10.1161/JAHA.121.022725 %0 Journal Article %J J Am Coll Cardiol %D 2021 %T Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. %A Yu, Bing %A Roberts, Mary B %A Raffield, Laura M %A Zekavat, Seyedeh Maryam %A Nguyen, Ngoc Quynh H %A Biggs, Mary L %A Brown, Michael R %A Griffin, Gabriel %A Desai, Pinkal %A Correa, Adolfo %A Morrison, Alanna C %A Shah, Amil M %A Niroula, Abhishek %A Uddin, Md Mesbah %A Honigberg, Michael C %A Ebert, Benjamin L %A Psaty, Bruce M %A Whitsel, Eric A %A Manson, JoAnn E %A Kooperberg, Charles %A Bick, Alexander G %A Ballantyne, Christie M %A Reiner, Alex P %A Natarajan, Pradeep %A Eaton, Charles B %K Aged %K Clonal Hematopoiesis %K Correlation of Data %K Demography %K DNA-Binding Proteins %K Female %K Heart Failure %K Humans %K Janus Kinase 2 %K Male %K Middle Aged %K Mutation %K Proportional Hazards Models %K Proto-Oncogene Proteins %K Repressor Proteins %K Risk Factors %K Stroke Volume %K Ventricular Dysfunction, Left %K Whole Exome Sequencing %X

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

%B J Am Coll Cardiol %V 78 %P 42-52 %8 2021 07 06 %G eng %N 1 %R 10.1016/j.jacc.2021.04.085 %0 Journal Article %J J Am Geriatr Soc %D 2021 %T Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study. %A Barzilay, Joshua I %A Bůzková, Petra %A Shlipak, Michael G %A Lyles, Mary F %A Bansal, Nisha %A Garimella, Pranav S %A Ix, Joachim H %A Kizer, Jorge R %A Strotmeyer, Elsa S %A Djoussé, Luc %A Biggs, Mary L %A Siscovick, David %A Mukamal, Kenneth J %X

PURPOSE: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

METHODS: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

RESULTS: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).

CONCLUSION: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.

%B J Am Geriatr Soc %8 2021 Aug 07 %G eng %R 10.1111/jgs.17388 %0 Journal Article %J J Am Soc Echocardiogr %D 2022 %T The association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study. %A Barasch, Eddy %A Gottdiener, John S %A Tressel, William %A Bartz, Traci M %A Bůzková, Petra %A Massera, Daniele %A DeFilippi, Christopher %A Biggs, Mary L %A Psaty, Bruce M %A Kizer, Jorge R %A Owens, David %X

BACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.

METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.

RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.

CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.

%B J Am Soc Echocardiogr %8 2022 Sep 09 %G eng %R 10.1016/j.echo.2022.08.013 %0 Journal Article %J Age Ageing %D 2022 %T The association of hearing problems with social network strength and depressive symptoms: the cardiovascular health study. %A Dobrota, Sylvie D %A Biggs, Mary L %A Pratt, Sheila %A Popat, Rita %A Odden, Michelle C %K Aged %K Depression %K Female %K Hearing Loss %K Humans %K Male %K Self Report %K Social Networking %X

BACKGROUND: research on the association between hearing impairment and psychosocial outcomes is not only limited but also yielded mixed results.

METHODS: we investigated associations between annual self-reports of hearing problems, depressive symptoms and social network strength among 5,888 adults from the Cardiovascular Health Study over a period of 9 years. Social network strength and depressive symptoms were defined using the Lubben Social Network Scale (LSNS), and the Center for Epidemiological Studies Depression Scale (CES-D).

RESULTS: hearing problems were associated with weaker social networks and more depressive symptoms. These association differed for prevalent versus incident hearing problems. Participants with prevalent hearing problems scored an adjusted 0.47 points lower (95% CI: -2.20, -0.71) on the LSNS and 0.71 points higher (95% CI: 0.23, 1.19) on the CES-D than those without hearing problems. Participants with incident hearing problems had a greater decline of 0.12 points (95% CI: -0.12, -0.03) per year in social network score than individuals with no hearing problems after adjusting for confounders. Females appeared to be more vulnerable to changes in social network strength than males (P-value for interaction = 0.02), but not for changes in depressive score. Accounting for social network score did not appear to attenuate the association between hearing problems and depressive score.

CONCLUSION: findings suggest that older adults with prevalent hearing problems may be more at risk for depression, but individuals with incident hearing problems may be at greater risk for a winnowing of their social network.

%B Age Ageing %V 51 %8 2022 Aug 02 %G eng %N 8 %R 10.1093/ageing/afac181 %0 Journal Article %J Diabetes Care %D 2022 %T The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study. %A Barzilay, Joshua I %A Tressel, William %A Biggs, Mary L %A Stein, Phyllis K %A Kizer, Jorge R %A Shitole, Sanyog G %A Bene-Alhasan, Yakubu %A Mukamal, Kenneth J %K Aged %K Autonomic Nervous System %K Blood Glucose %K Diabetes Mellitus %K Glucose %K Heart Rate %K Humans %K Hypotension, Orthostatic %K Insulin Resistance %X

OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.

RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change.

RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change.

CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.

%B Diabetes Care %V 45 %P 2376-2382 %8 2022 10 01 %G eng %N 10 %R 10.2337/dc22-0553 %0 Journal Article %J Psychosom Med %D 2022 %T Associations of modifiable behavioral risk factor combinations at 65-74 years old with cognitive healthspan over 20 years. %A Smagula, Stephen F %A Biggs, Mary L %A Jacob, Mini E %A Rawlings, Andreea M %A Odden, Michelle C %A Arnold, Alice %A Newman, Anne B %A Buysse, Daniel J %X

OBJECTIVE: Behavioral risk factors for dementia tend to co-occur and inter-relate, especially poor diet, physical inactivity, sleep disturbances, and depression. Having multiple of these modifiable behavioral risk factors (MBRFs) may predict a particularly shortened cognitive healthspan, and therefore, may signal high-risk status/high intervention need.

METHODS: This secondary analyses of data from the Cardiovascular Health Study included 3149 participants aged 65-74 years (mean age = 69.5, standard deviation (SD) = 2.5; 59.6% female). MBRF exposures were self-reports regarding: (1) diet, (2) activity, (3) sleep, and (4) depression symptoms. We primarily analyzed MBRF counts. Over up to 26 years of follow-up, we assessed the: (1) number of remaining cognitively healthy life years (CHLYs); and (2) percentage of remaining life years (LYs) that were CHLYs (%CHLY). We estimated CHLYs as time before a dementia diagnosis, cognitive screener scores indicating impairment, proxy port indicating significant cognitive decline, or dementia medication use.

RESULTS: Participants averaged a remaining 16 LYs (SD = 7), 12.2 CHLYs (SD = 6.6), and 78.1% of LYs being CHLYs (SD = 25.6). Compared with having no MBRFs, having one was associated with ~1 less LY and CHLY, but not a relatively lower %CHLY. In contrast, having 3+ MBRFs was associated with about 2-3 fewer LYs and CHLYs as well as about 6% lower %CHLY (95% confidence interval: -9.0, -2.5 %CHLYs), p = 0.001).

CONCLUSIONS: MBRF-related reductions in the cognitive healthspan are most apparent when people have multiple MBRFs. Future research is needed to determine if/how behavioral risks converge mechanistically, and if dementia prevention efficacy improves when targeting MBRF combinations.

%B Psychosom Med %8 2022 Jun 28 %G eng %R 10.1097/PSY.0000000000001100 %0 Journal Article %J J Am Heart Assoc %D 2022 %T Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study. %A Njoroge, Joyce N %A Tressel, William %A Biggs, Mary L %A Matsumoto, Alvin M %A Smith, Nicholas L %A Rosenberg, Emily %A Hirsch, Calvin H %A Gottdiener, John S %A Mukamal, Kenneth J %A Kizer, Jorge R %K Aged %K Androgens %K Cardiovascular Diseases %K Dihydrotestosterone %K Estradiol %K Heart Failure %K Humans %K Male %K Sex Hormone-Binding Globulin %K Testosterone %X

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76±5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95% CI, 0.99-1.26]), total DHT (HR, 1.10 [95% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

%B J Am Heart Assoc %V 11 %P e026953 %8 2022 Nov %G eng %N 21 %R 10.1161/JAHA.122.026953 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Am J Epidemiol %D 2022 %T Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults. %A Shitole, Sanyog G %A Biggs, Mary L %A Ix, Joachim H %A Fretts, Amanda M %A Tracy, Russell P %A Siscovick, David S %A Djoussé, Luc %A Mukamal, Kenneth J %A Kizer, Jorge R %K Aged %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Fasting %K Fatty Acids, Nonesterified %K Female %K Glucose %K Humans %K Insulin %K Insulin Resistance %K Male %K Prospective Studies %X

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

%B Am J Epidemiol %V 191 %P 1235-1247 %8 2022 Jun 27 %G eng %N 7 %R 10.1093/aje/kwac044 %0 Journal Article %J Kidney Int %D 2022 %T Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. %A Gorski, Mathias %A Rasheed, Humaira %A Teumer, Alexander %A Thomas, Laurent F %A Graham, Sarah E %A Sveinbjornsson, Gardar %A Winkler, Thomas W %A Günther, Felix %A Stark, Klaus J %A Chai, Jin-Fang %A Tayo, Bamidele O %A Wuttke, Matthias %A Li, Yong %A Tin, Adrienne %A Ahluwalia, Tarunveer S %A Arnlöv, Johan %A Åsvold, Bjørn Olav %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Biino, Ginevra %A Böhnke, Michael %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Brumpton, Ben %A Carroll, Robert J %A Chaker, Layal %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Chu, Audrey Y %A Ciullo, Marina %A Cocca, Massimiliano %A Cook, James P %A Coresh, Josef %A Cusi, Daniele %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Evans, Michele K %A Feitosa, Mary F %A Franke, Andre %A Freitag-Wolf, Sandra %A Fuchsberger, Christian %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Giedraitis, Vilmantas %A Gieger, Christian %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hishida, Asahi %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Holm, Hilma %A Hoppmann, Anselm %A Horn, Katrin %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Karabegović, Irma %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Laakso, Markku %A Lange, Leslie A %A Lehtimäki, Terho %A Li, Man %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Matias-Garcia, Pamela R %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Morris, Andrew P %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Naito, Mariko %A Nakatochi, Masahiro %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Nutile, Teresa %A O'Donoghue, Michelle L %A O'Connell, Jeffrey %A Olafsson, Isleifur %A Orho-Melander, Marju %A Parsa, Afshin %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Pirastu, Mario %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Ruggiero, Daniela %A Ryan, Kathleen A %A Sabanayagam, Charumathi %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Scholz, Markus %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Sieber, Karsten B %A Sim, Xueling %A Sims, Mario %A Snieder, Harold %A Stanzick, Kira J %A Thorsteinsdottir, Unnur %A Stocker, Hannah %A Strauch, Konstantin %A Stringham, Heather M %A Sulem, Patrick %A Szymczak, Silke %A Taylor, Kent D %A Thio, Chris H L %A Tremblay, Johanne %A Vaccargiu, Simona %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Wakai, Kenji %A Waldenberger, Melanie %A Wallentin, Lars %A Wallner, Stefan %A Wang, Judy %A Waterworth, Dawn M %A White, Harvey D %A Willer, Cristen J %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yerges-Armstrong, Laura M %A Zimmermann, Martina %A Zonderman, Alan B %A Bergler, Tobias %A Stefansson, Kari %A Böger, Carsten A %A Pattaro, Cristian %A Köttgen, Anna %A Kronenberg, Florian %A Heid, Iris M %X

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

%B Kidney Int %8 2022 Jun 16 %G eng %R 10.1016/j.kint.2022.05.021 %0 Journal Article %J iScience %D 2022 %T Genome-wide analyses identify as a susceptibility locus for premature atrial contraction frequency. %A Thériault, Sébastien %A Imboden, Medea %A Biggs, Mary L %A Austin, Thomas R %A Aeschbacher, Stefanie %A Schaffner, Emmanuel %A Brody, Jennifer A %A Bartz, Traci M %A Risch, Martin %A Grossmann, Kirsten %A Lin, Henry J %A Soliman, Elsayed Z %A Post, Wendy S %A Risch, Lorenz %A Krieger, Jose E %A Pereira, Alexandre C %A Heckbert, Susan R %A Sotoodehnia, Nona %A Probst-Hensch, Nicole M %A Conen, David %X

Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the gene. The lead variant, rs7373862, located in an intron of , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10). However, several AF risk loci, including , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.

%B iScience %V 25 %P 105210 %8 2022 Oct 21 %G eng %N 10 %R 10.1016/j.isci.2022.105210 %0 Journal Article %J Cardiovasc Diabetol %D 2022 %T Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Biggs, Mary L %A Kizer, Jorge R %A Shah, Sanjiv J %A Psaty, Bruce %A Carnethon, Mercedes %A Gottdiener, John S %A Siscovick, David %A Mukamal, Kenneth J %K Aged %K Cross-Sectional Studies %K Female %K Glucose %K Humans %K Insulin Resistance %K Male %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.

RESULTS: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03-0.33).

CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.

%B Cardiovasc Diabetol %V 21 %P 112 %8 2022 Jun 20 %G eng %N 1 %R 10.1186/s12933-022-01547-z %0 Journal Article %J JAMA Netw Open %D 2022 %T Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults. %A Shivakoti, Rupak %A Biggs, Mary L %A Djoussé, Luc %A Durda, Peter Jon %A Kizer, Jorge R %A Psaty, Bruce %A Reiner, Alex P %A Tracy, Russell P %A Siscovick, David %A Mukamal, Kenneth J %K Adult %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Dietary Fiber %K Female %K Humans %K Inflammation %K Middle Aged %K Risk Factors %X

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1% (n = 3) were Asian or Pacific Islander, 4.4% (n = 183) were Black, 0.3% (n = 12) were Native American, 95.0% (n = 3918) were White, and 0.2% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4%]; and 3942 individuals of other races and ethnicitites [95.6%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5% for interleukin 18 to 14.2% for C-reactive protein, and 16.1% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

%B JAMA Netw Open %V 5 %P e225012 %8 2022 Mar 01 %G eng %N 3 %R 10.1001/jamanetworkopen.2022.5012 %0 Journal Article %J J Am Heart Assoc %D 2022 %T Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts. %A Lamprea-Montealegre, Julio A %A Arnold, Alice M %A McClelland, Robyn L %A Mukamal, Kenneth J %A Djoussé, Luc %A Biggs, Mary L %A Siscovick, David S %A Tracy, Russell P %A Beisswenger, Paul J %A Psaty, Bruce M %A Ix, Joachim H %A Kizer, Jorge R %K Atherosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Glycation End Products, Advanced %K Humans %K Middle Aged %K Risk Factors %X

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.

%B J Am Heart Assoc %V 11 %P e024012 %8 2022 08 02 %G eng %N 15 %R 10.1161/JAHA.121.024012 %0 Journal Article %J Am J Clin Nutr %D 2022 %T Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: The Cardiovascular Health Study. %A Carew, Allie S %A Mekary, Rania A %A Kirkland, Susan %A Theou, Olga %A Siddiqi, Ferhan %A Urquhart, Robin %A George, Michelle %A Blanchard, Chris %A Biggs, Mary L %A Djoussé, Luc %A Mukamal, Kenneth J %A Cahill, Leah E %X

BACKGROUND: No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults due to limited studies.

OBJECTIVE: We sought to prospectively assess relationships between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on gender or cardiometabolic risk factors.

METHODS: Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3,747 older adults (aged ≥65 years) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 years. Multivariable-adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from Cox proportional hazards models were used to quantify associations with T2DM.

RESULTS: Most CHS participants (median age: 74 years; interquartile range: 71, 78) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00-09:00 hours, which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed between breakfast frequency and risk of T2DM. Compared to participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (0.61; 0.39, 0.95) but not in those without (0.83; 0.50, 1.38)). No associations between eating frequency or timing and T2DM were observed within other pre-specified subgroups.

CONCLUSIONS: Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, while a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.

%B Am J Clin Nutr %8 2022 Apr 05 %G eng %R 10.1093/ajcn/nqac087 %0 Journal Article %J Eur J Epidemiol %D 2022 %T Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. %A Austin, Thomas R %A McHugh, Caitlin P %A Brody, Jennifer A %A Bis, Joshua C %A Sitlani, Colleen M %A Bartz, Traci M %A Biggs, Mary L %A Bansal, Nisha %A Bůzková, Petra %A Carr, Steven A %A deFilippi, Christopher R %A Elkind, Mitchell S V %A Fink, Howard A %A Floyd, James S %A Fohner, Alison E %A Gerszten, Robert E %A Heckbert, Susan R %A Katz, Daniel H %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Longstreth, W T %A McKnight, Barbara %A Mei, Hao %A Mukamal, Kenneth J %A Newman, Anne B %A Ngo, Debby %A Odden, Michelle C %A Vasan, Ramachandran S %A Shojaie, Ali %A Simon, Noah %A Smith, George Davey %A Davies, Neil M %A Siscovick, David S %A Sotoodehnia, Nona %A Tracy, Russell P %A Wiggins, Kerri L %A Zheng, Jie %A Psaty, Bruce M %X

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

%B Eur J Epidemiol %8 2022 Jul 05 %G eng %R 10.1007/s10654-022-00888-z %0 Journal Article %J Cancer Epidemiol %D 2022 %T Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS). %A Sillah, Arthur %A Watson, Nathaniel F %A Peters, Ulrike %A Biggs, Mary L %A Nieto, F Javier %A Li, Christopher I %A Gozal, David %A Thornton, Timothy %A Barrie, Sonnah %A Phipps, Amanda I %X

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.

%B Cancer Epidemiol %V 76 %P 102057 %8 2022 Feb %G eng %R 10.1016/j.canep.2021.102057 %0 Journal Article %J Ann Intern Med %D 2023 %T Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses. %A Marriott, Ross J %A Murray, Kevin %A Adams, Robert J %A Antonio, Leen %A Ballantyne, Christie M %A Bauer, Douglas C %A Bhasin, Shalender %A Biggs, Mary L %A Cawthon, Peggy M %A Couper, David J %A Dobs, Adrian S %A Flicker, Leon %A Handelsman, David J %A Hankey, Graeme J %A Hannemann, Anke %A Haring, Robin %A Hsu, Benjumin %A Karlsson, Magnus %A Martin, Sean A %A Matsumoto, Alvin M %A Mellström, Dan %A Ohlsson, Claes %A O'Neill, Terence W %A Orwoll, Eric S %A Quartagno, Matteo %A Shores, Molly M %A Steveling, Antje %A Tivesten, Åsa %A Travison, Thomas G %A Vanderschueren, Dirk %A Wittert, Gary A %A Wu, Frederick C W %A Yeap, Bu B %X

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).

%B Ann Intern Med %8 2023 Aug 29 %G eng %R 10.7326/M23-0342 %0 Journal Article %J Alzheimers Dement (Amst) %D 2023 %T Neighborhood greenspace and neighborhood income associated with white matter grade worsening: Cardiovascular Health Study. %A Besser, Lilah M %A Lovasi, Gina S %A Zambrano, Joyce Jimenez %A Camacho, Simone %A Dhanekula, Devi %A Michael, Yvonne L %A Garg, Parveen %A Hirsch, Jana A %A Siscovick, David %A Hurvitz, Philip M %A Biggs, Mary L %A Galvin, James E %A Bartz, Traci M %A Longstreth, W T %X

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.

%B Alzheimers Dement (Amst) %V 15 %P e12484 %8 2023 Oct-Dec %G eng %N 4 %R 10.1002/dad2.12484 %0 Journal Article %J Am J Prev Med %D 2023 %T Time-Varying Food Retail and Incident Disease in the Cardiovascular Health Study. %A Lovasi, Gina S %A Boise, Sarah %A Jogi, Siddharth %A Hurvitz, Philip M %A Rundle, Andrew G %A Diez, Julia %A Hirsch, Jana A %A Fitzpatrick, Annette %A Biggs, Mary L %A Siscovick, David S %X

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.

%B Am J Prev Med %8 2023 Mar 05 %G eng %R 10.1016/j.amepre.2023.02.001 %0 Journal Article %J Heart %D 2023 %T Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults. %A Massera, Daniele %A Bartz, Traci M %A Biggs, Mary L %A Sotoodehnia, Nona %A Reiner, Alexander P %A Semba, Richard D %A Gottdiener, John S %A Psaty, Bruce M %A Owens, David S %A Kizer, Jorge R %X

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.

%B Heart %8 2023 Jul 18 %G eng %R 10.1136/heartjnl-2023-322709 %0 Journal Article %J Nat Commun %D 2024 %T 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. %A Scholz, Markus %A Horn, Katrin %A Pott, Janne %A Wuttke, Matthias %A Kühnapfel, Andreas %A Nasr, M Kamal %A Kirsten, Holger %A Li, Yong %A Hoppmann, Anselm %A Gorski, Mathias %A Ghasemi, Sahar %A Li, Man %A Tin, Adrienne %A Chai, Jin-Fang %A Cocca, Massimiliano %A Wang, Judy %A Nutile, Teresa %A Akiyama, Masato %A Åsvold, Bjørn Olav %A Bansal, Nisha %A Biggs, Mary L %A Boutin, Thibaud %A Brenner, Hermann %A Brumpton, Ben %A Burkhardt, Ralph %A Cai, Jianwen %A Campbell, Archie %A Campbell, Harry %A Chalmers, John %A Chasman, Daniel I %A Chee, Miao Ling %A Chee, Miao Li %A Chen, Xu %A Cheng, Ching-Yu %A Cifkova, Renata %A Daviglus, Martha %A Delgado, Graciela %A Dittrich, Katalin %A Edwards, Todd L %A Endlich, Karlhans %A Michael Gaziano, J %A Giri, Ayush %A Giulianini, Franco %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hartman, Catharina A %A Hayward, Caroline %A Heid, Iris M %A Hellwege, Jacklyn N %A Holleczek, Bernd %A Holm, Hilma %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Isermann, Berend %A Jonas, Jost B %A Joshi, Peter K %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kastarinen, Mika %A Khor, Chiea Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Körner, Antje %A Kovacs, Peter %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kuokkanen, Mikko %A Kähönen, Mika %A Lange, Leslie A %A Lash, James P %A Lehtimäki, Terho %A Li, Hengtong %A Lin, Bridget M %A Liu, Jianjun %A Loeffler, Markus %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Martin, Nicholas G %A Matsuda, Koichi %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A März, Winfried %A Nauck, Matthias %A Nikus, Kjell %A Nolte, Ilja M %A Noordam, Raymond %A Okada, Yukinori %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Perola, Markus %A Pirastu, Nicola %A Polasek, Ozren %A Porteous, David J %A Poulain, Tanja %A Psaty, Bruce M %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rasheed, Humaira %A Reilly, Dermot F %A Rice, Kenneth M %A Richmond, Anne %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Schneiderman, Neil %A Schöttker, Ben %A Sims, Mario %A Snieder, Harold %A Stark, Klaus J %A Stefansson, Kari %A Stocker, Hannah %A Stumvoll, Michael %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Svensson, Per O %A Tai, E-Shyong %A Taylor, Kent D %A Tayo, Bamidele O %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomas, Laurent F %A Tremblay, Johanne %A Tönjes, Anke %A van der Most, Peter J %A Vitart, Veronique %A Völker, Uwe %A Wang, Ya Xing %A Wang, Chaolong %A Wei, Wen Bin %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Winkler, Thomas W %A Wong, Tien-Yin %A Woodward, Mark %A Sim, Xueling %A Chu, Audrey Y %A Feitosa, Mary F %A Thorsteinsdottir, Unnur %A Hung, Adriana M %A Teumer, Alexander %A Franceschini, Nora %A Parsa, Afshin %A Köttgen, Anna %A Schlosser, Pascal %A Pattaro, Cristian %K Androgens %K Chromosomes, Human, X %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Kidney %K Male %K Polymorphism, Single Nucleotide %K Response Elements %K Tetraspanins %X

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.

%B Nat Commun %V 15 %P 586 %8 2024 Jan 18 %G eng %N 1 %R 10.1038/s41467-024-44709-1