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1.  Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels 
van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Deelen, Joris | Isaacs, Aaron | Medina-Gomez, Carolina | Mbarek, Hamdi | Kanterakis, Alexandros | Trompet, Stella | Postmus, Iris | Verweij, Niek | van Enckevort, David J. | Huffman, Jennifer E. | White, Charles C. | Feitosa, Mary F. | Bartz, Traci M. | Manichaikul, Ani | Joshi, Peter K. | Peloso, Gina M. | Deelen, Patrick | van Dijk, Freerk | Willemsen, Gonneke | de Geus, Eco J. | Milaneschi, Yuri | Penninx, Brenda W.J.H. | Francioli, Laurent C. | Menelaou, Androniki | Pulit, Sara L. | Rivadeneira, Fernando | Hofman, Albert | Oostra, Ben A. | Franco, Oscar H. | Leach, Irene Mateo | Beekman, Marian | de Craen, Anton J.M. | Uh, Hae-Won | Trochet, Holly | Hocking, Lynne J. | Porteous, David J. | Sattar, Naveed | Packard, Chris J. | Buckley, Brendan M. | Brody, Jennifer A. | Bis, Joshua C. | Rotter, Jerome I. | Mychaleckyj, Josyf C. | Campbell, Harry | Duan, Qing | Lange, Leslie A. | Wilson, James F. | Hayward, Caroline | Polasek, Ozren | Vitart, Veronique | Rudan, Igor | Wright, Alan F. | Rich, Stephen S. | Psaty, Bruce M. | Borecki, Ingrid B. | Kearney, Patricia M. | Stott, David J. | Adrienne Cupples, L. | Jukema, J. Wouter | van der Harst, Pim | Sijbrands, Eric J. | Hottenga, Jouke-Jan | Uitterlinden, Andre G. | Swertz, Morris A. | van Ommen, Gert-Jan B. | de Bakker, Paul I.W. | Eline Slagboom, P. | Boomsma, Dorret I. | Wijmenga, Cisca | van Duijn, Cornelia M.
Nature Communications  2015;6:6065.
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
Frequencies of rare variants fluctuate over populations, hampering gene discovery. Here the authors use a population-specific reference panel, the Genome of the Netherlands, to discover four novel loci involved in lipid metabolism, including an exonic variant in ABCA6.
PMCID: PMC4366498  PMID: 25751400
2.  Relation of Plasma Total and High-Molecular-Weight Adiponectin to New-Onset Heart Failure in Adults ≥ 65 Years of Age (From the Cardiovascular Health Study) 
The American journal of cardiology  2013;113(2):328-334.
Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine’s association with new-onset HF remains less well defined. We investigated the associations of total and HMW adiponectin with incident HF (n=780) and, in a subset, echocardiographic parameters in a community-based cohort of adults 65 and older. Total and high molecular weight (HMW) adiponectin were measured in 3,228 subjects without prevalent HF or CVD. The relationships of total and HMW adiponectin with HF were nonlinear, with significant associations observed only above their medians (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios (HR) per standard deviation (SD) increment in total adiponectin were 0.93 (95% confidence interval [CI]=0.72–1.21) below the median and 1.25 (95% CI=1.14–1.38) above it. There was a suggestion of effect modification by body mass index (BMI), whereby the association appeared strongest among participants with lower BMIs. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relationships with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.
PMCID: PMC3968249  PMID: 24169012
Adiponectin; Aging; Heart Failure
3.  Cardiomyocyte Injury Assessed by a Highly Sensitive Troponin Assay and Sudden Cardiac Death in the Community: The Cardiovascular Health Study 
To study the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).
The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.
Levels of cardiac Troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3089 subjects. All deaths, including SCD, were adjudicated by a central events committee.
Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD [Hazard ratio (HR) for +1Log(hsTnT) 2.04, 95% confidence interval (CI) 1.78–2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR 1.30, 95%CI 1.05–1.62), as well as for incident heart failure and myocardial infarction (HR 1.26, 95%CI 1.01–1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [Fully-adjusted HRs 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT≥12.10 vs. 5.01–12.09 vs. ≤5.00 pg/mL, respectively; Ptrend=0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (Fully-adjusted HR for +1pg/ml per year increase from baseline 1.03, 95%CI 1.01–1.06).
The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.
PMCID: PMC4157919  PMID: 23973690
death; sudden; myocytes; general population
4.  Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes 
Diabetes Care  2013;36(10):3121-3127.
Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.
Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993.
Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P < 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant.
Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
PMCID: PMC3781539  PMID: 23801724
5.  Comparison of Characteristics and Outcomes of Asymptomatic Versus Symptomatic Left Ventricular Dysfunction in Subjects 65 Years Old or Older (from the Cardiovascular Health Study) 
The American journal of cardiology  2011;107(11):1667-1674.
Although asymptomatic left ventricular (LV) systolic dysfunction (ALVSD) is common, its phenotype and prognosis for incident heart failure (HF) and mortality are insufficiently understood. Echocardiography was done in 5,649 participants in the Cardiovascular Health Study (age 73.0 ± 5.6 years, 57.6% women). The clinical characteristics and cardiovascular risk factors of the participants with ALVSD were compared to those with normal LV function (ejection fraction ≥55%) and with symptomatic LV systolic dysfunction (SLVSD; ejection fraction <55% and a history of HF). Cox proportional hazards models were used to estimate the risk of incident HF and mortality in those with ALVSD. Also, comparisons were made among the LV ejection fraction subgroups using previously validated cutoff values (<45% and 45% to 55%), adjusting for the demographic and cardiovascular disease risk factors. Those with ALVSD (7.3%) were more likely to have cardiovascular risk factors than those in the reference group (without LV dysfunction or symptomatic HF) but less likely than those with SLVSD. The HF rate was 24 occurrences per 1,000 person-years in the reference group and 57 occurrences per 1,000 person-years in those with ALVSD. The HF rate was 45 occurrences per 1,000 person-years for those with ALVSD and mildly impaired LV dysfunction and 93 occurrences per 1,000 person-years for those with ALVSD and moderate to severe LV dysfunction. The mortality rate was 51 deaths per 1,000 person-years in the reference group, 90 deaths per 1,000 person-years in the ALVSD group, and 156 deaths per 1,000 person-years in the SLVSD group. Adjusting for covariates, compared to the reference group, ALVSD was associated with an increased risk of incident HF (hazard ratio 1.60,95% confidence interval 1.35 to 1.91), cardiovascular mortality (hazard ratio 2.13, 95% confidence interval 1.81 to 2.51), and all-cause mortality (hazard ratio 1.46, 95% confidence interval 1.29 to 1.64). In conclusion, subjects with ALVSD are characterized by a greater prevalence of cardiovascular risk factors and co-morbidities than those with normal LV function and without HF. However, the prevalence is lower than in those with SLVSD. Patients with ALVSD are at an increased risk of HF and mortality, particularly those with greater severity of LV impairment.
PMCID: PMC4143416  PMID: 21575752
6.  Association of Cardiac Annular / Valvular Calcification with Brain Findings on Magnetic Resonance Imaging in Community Dwelling Older Adults: the Cardiovascular Health Study 
The objective of this study is to investigate the association of mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVSc) with covert magnetic resonance imaging (MRI)-defined brain infarcts.
Clinically silent brain infarcts defined by MRI are associated with increased risk of cognitive decline, dementia, and future overt stroke. Left sided cardiac valvular / annular calcifications are suspected as risk factors for clinical ischemic stroke.
2,680 Cardiovascular Health Study participants without clinical history of stroke or transient ischemic attack underwent both brain MRI (1992–93) and echocardiography (1994–95).
The mean age of the participants was 74.5 years ± 4.8 and 39.3% were men. The presence of any annular / valvular calcification (either MAC or AAC or AVSc), MAC alone, or AAC alone were significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, HDL-cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular / valve calcification remained associated with covert brain infarcts [RR 1.24 (95% CI 1.05, 1.47)]. The degree of annular / valvular calcification severity showed a direct relation with the presence of covert MRI findings.
Left-sided cardiac annular / valvular calcification are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening on the progression of annular / valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk of cognitive impairment and future stroke.
PMCID: PMC4104125  PMID: 21596233
Covert Brain Infarcts; Aortic Valve; Mitral Valve; Calcification; Epidemiology
7.  Fetuin-A, Type 2 Diabetes, and Risk of Cardiovascular Disease in Older Adults 
Diabetes Care  2013;36(5):1222-1228.
Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.
This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.
Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88–0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93–1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85–0.97) and 0.87 (0.79–0.95), respectively].
The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
PMCID: PMC3631840  PMID: 23250801
8.  Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study 
European Journal of Heart Failure  2012;15(4):394-399.
To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.
Methods and results
In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25–1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01–1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.
An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
PMCID: PMC3707430  PMID: 23223158
Epidemiology; Adiposity; Heart failure; Fatty acid-binding protein 4
9.  Adiposity and incident heart failure in older adults: the Cardiovascular Health Study 
Obesity (Silver Spring, Md.)  2011;20(9):1936-1941.
While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident heart failure in older adults. We sought to examine the association between waist circumference and incident heart failure and assess whether sex modifies the relation between waist circumference and heart failure. Prospective study using data on 4861 participants of the Cardiovascular Health Study (1989 to 2007). Heart failure was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio. The mean age was 73.0 y for men and 72.3 y for women; 42.5% were men and 15.3% were African-Americans. Waist circumference was positively associated with an increased risk of HF: each standard deviation of waist circumference was associated with a 14% increased risk of HF (95% CI: 3% to 26%) in a multivariable model. There was not a statistically significant sex-by-waist circumference interaction (p=0.081). Body mass index was positively associated with incident HF [HR: 1.22 (95% CI: 1.15–1.29) per standard deviation increase of body mass index], however, this association was attenuated and became non-statistically significant upon additional adjustment for waist circumference [HR: 1.09 (95% CI: 0.99–1.21)]. In conclusion, a higher waist circumference is associated with an increased risk of heart failure independent of body mass index in community-living older men and women.
PMCID: PMC3429627  PMID: 22016094
Epidemiology; heart failure; adiposity; risk factors
10.  Plasma Fatty Acid–Binding Protein 4, Nonesterified Fatty Acids, and Incident Diabetes in Older Adults 
Diabetes Care  2012;35(8):1701-1707.
To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.
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.
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/m2 (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (Ptrend = 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 (Ptrend = 0.03).
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.
PMCID: PMC3402261  PMID: 22584136
11.  Plasma Free Fatty Acids and Risk of Atrial Fibrillation (From the Cardiovascular Health Study) 
The American Journal of Cardiology  2012;110(2):212-216.
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million people in the USA and 4.5 million people in the European Union. It is unclear whether plasma free fatty acids (FFA) influence the risk of AF among older adults. The aim of this study was to prospectively examine the association between plasma FFA and incident AF in a prospective cohort of 4,175 men and women aged ≥65 years from the Cardiovascular Health Study. Plasma concentrations of FFA were measured in duplicate during the 1992-93 examination. Incident AF was ascertained based on study EKG and hospitalization records during follow up. We used Cox regression to estimate relative risks of AF. The average age at baseline was 74.6 ± 5.1 years. During a mean follow up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFA. There was a positive association between plasma FFA and the risk of AF. Multivariable adjusted hazard ratios (95% CI) for incident AF were 1.00 (ref), 1.02 (0.85-1.21), 1.05 (0.88-1.26), and 1.29 (1.08-1.55) from lowest to the highest quartile of FFA, respectively. In a secondary analysis restricted to the first five years of follow up, this association persisted. In conclusion, our data show an elevated risk of AF with higher plasma FFA among community dwelling older adults.
PMCID: PMC3383877  PMID: 22503582
Free Fatty Acids; Atrial Fibrillation; Risk Factors; Epidemiology
12.  Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study 
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32–2.33) and extreme variability (HR 1.89, CI 1.47–2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88–1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).
Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
PMCID: PMC2773814  PMID: 19713299
DHEA; DHEAS; Mortality; Aging; Elderly

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