Nicholas S. Roetker

DNA methylation-based measures of biological age: meta-analysis predicting time to death.

Estimates of biological age based on DNA methylation patterns, often referred to as “epigenetic age”, “DNAm age”, have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2×10−9), independent of chronological age, even after adjusting for additional risk factors (p<5.4×10−4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5×10−43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

Chronic stress, depressive symptoms, anger, hostility, and risk of stroke and transient ischemic attack in the multi-ethnic study of atherosclerosis.

Background and Purpose— This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults. Methods— Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years. Results— One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend ⩽0.02) but not for trait anger (P>0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16–2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11–2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29–3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor–adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables. Conclusions— Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.

Prospective study of sickle cell trait and venous thromboembolism incidence.

Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established.

DNA Methylation–Based Measures of Biological Aging

Abstract Aging is associated with profound changes in DNA methylation. Recent studies have used DNA methylation to build very accurate age predictors, also named “epigenetic clocks,” that deviate from chronological age by only a few years. The individual-specific deviation from chronological age—represented by the residual from a regression of predicted age on chronological age—has been interpreted as a biomarker of biological aging and referred to as “age acceleration” or “epigenetic aging.” Numerous studies have investigated such measures of biological aging based on DNA methylation and have found them to be associated with mortality, disease, and risk factors for disease. Although the biological significance of age acceleration measures is not yet fully characterized, they represent a promising tool for epidemiologists and clinicians to study health. Other attempts to characterize how age-associated methylation changes relate to health are likely to emerge in the near future.

Blood Lipids and the Incidence of Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis and the Framingham Heart Study

Background Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain. Methods and Results We studied 7142 men and women from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid‐lowering medications. Total cholesterol, high‐density lipoprotein and low‐density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow‐up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study‐specific results were meta‐analyzed using inverse of variance weighting. During 9.6 years of mean follow‐up, 480 AF cases were identified. In a combined analysis of multivariable‐adjusted results from both cohorts, high levels of high‐density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels ≥60 mg/dL versus <40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels ≥200 mg/dL versus <150 mg/dL). Total cholesterol and low‐density lipoprotein cholesterol were not associated with the risk of AF. Conclusion In these 2 community‐based cohorts, high‐density lipoprotein cholesterol and triglycerides but not low‐density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors.

Lifetime Risk and Risk Factors for Abdominal Aortic Aneurysm in a 24-Year Prospective Study The ARIC Study (Atherosclerosis Risk in Communities)

Objective—Abdominal aortic aneurysm (AAA) is an important vascular disease in older adults, but data on lifetime risk of AAA are sparse. We examined lifetime risk of AAA in a community-based cohort and prospectively assessed the association between midlife cardiovascular risk factors and AAAs. Approach and Results—In ARIC study (Atherosclerosis Risk in Communities), 15 792 participants were recruited at visit 1 in 1987 to 1989 and followed up through 2013. Longitudinal smoking status was defined using smoking behavior ascertained from visit 1 (1987–1989) to visit 4 (1996–1998). We followed up participants for incident, clinical AAAs using hospital discharge diagnoses, Medicare outpatient diagnoses, or death certificates through 2011 and identified 590 incident AAAs. An abdominal ultrasound was conducted in 2011 to 2013 in 5911 surviving participants, and 75 asymptomatic AAAs were identified. We estimated the lifetime risk of AAA from the index age 45 years through 85 years of age. At age 45, the lifetime risk for AAA was 5.6% (95% confidence interval, 4.8–6.1) and was higher in men (8.2%) and current smokers (10.5%). Smokers who quit smoking between visit 1 and visit 4 had a 29% lower AAA lifetime risk compared with continuous smokers but had a higher risk than pre-visit 1 quitters. The lifetime risk of rupture or medical intervention was 1.6% (95% confidence interval, 1.2–1.8). Smoking, white race, male sex, greater height, and greater low-density lipoprotein or total cholesterol were associated with an increased risk of clinical AAA and asymptomatic AAA. Conclusions—At least 1 in 9 middle-aged current smokers developed AAA in their lifetime. Smoking cessation reduced the lifetime risk of AAA.

Perceived Discrimination and Incident Cardiovascular Events The Multi-Ethnic Study of Atherosclerosis

Perceived discrimination is positively related to cardiovascular disease (CVD) risk factors; its relationship with incident CVD is unknown. Using data from the Multi-Ethnic Study of Atherosclerosis, a population-based multiethnic cohort study of 6,508 adults aged 45-84 years who were initially free of clinical CVD, we examined lifetime discrimination (experiences of unfair treatment in 6 life domains) and everyday discrimination (frequency of day-to-day occurrences of perceived unfair treatment) in relation to incident CVD. During a median 10.1 years of follow-up (2000-2011), 604 incident events occurred. Persons reporting lifetime discrimination in ≥2 domains (versus none) had increased CVD risk, after adjustment for race/ethnicity and sociodemographic factors, behaviors, and traditional CVD risk factors (hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.09, 1.70) and after control for chronic stress and depressive symptoms (HR = 1.28, 95% CI: 1.01, 1.60). Reported discrimination in 1 domain was unrelated to CVD (HR = 1.05, 95% CI: 0.86, 1.30). There were no differences by race/ethnicity, age, or sex. In contrast, everyday discrimination interacted with sex (P = 0.03). Stratified models showed increased risk only among men (for each 1-standard deviation increase in score, adjusted HR = 1.14, 95% CI: 1.03, 1.27); controlling for chronic stress and depressive symptoms slightly reduced this association (HR = 1.11, 95% CI: 0.99, 1.25). This study suggests that perceived discrimination is adversely related to CVD risk in middle-aged and older adults.

Prediction of Atrial Fibrillation in a Racially Diverse Cohort: The Multi‐Ethnic Study of Atherosclerosis (MESA)

Background Existing equations for prediction of atrial fibrillation (AF) have been developed and validated in white and African‐American populations. Whether these models adequately predict AF in more racially and ethnically diverse populations is unknown. Methods and Results We studied 6663 men and women 45 to 84 years of age without AF at baseline (2000–2002) enrolled in the Multi‐Ethnic Study of Atherosclerosis (MESA). Of these, 38% were non‐Hispanic whites, 28% non‐Hispanic African Americans, 22% Hispanics, and 12% Chinese Americans. AF during follow‐up was ascertained from hospitalization discharge codes through 2012. Information collected at baseline was used to calculate predicted 5‐year risk of AF using the previously published simple CHARGE‐AF model, which only includes clinical variables, and a biomarker‐enriched CHARGE‐AF model, which also considers levels of circulating N‐terminal of the prohormone B‐type natriuretic peptide and C‐reactive protein. For comparison purposes, we also assessed performance of the 10‐year Framingham AF model. During a mean follow‐up of 10.2 years, 351 cases of AF were identified. The C‐statistic of the CHARGE‐AF models were 0.779 (95% CI, 0.744–0.814) for the simple model and 0.825 (95% CI, 0.791–0.860) for the biomarker‐enriched model. Calibration was adequate in the biomarker‐enriched model (χ2=7.9; P=0.55), but suboptimal in the simple model (χ2=25.6; P=0.002). In contrast, the 10‐year Framingham score had a C‐statistic (95% CI) of 0.746 (0.720–0.771) and showed poor calibration (χ2=57.4; P<0.0001). Conclusion The CHARGE‐AF risk models adequately predicted 5‐year AF risk in a large multiethnic cohort. These models could be useful to select high‐risk individuals for AF screening programs or for primary prevention trials in diverse populations.

Serum 25‐hydroxyvitamin D and risk of venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study

Some evidence suggests that an inadequate vitamin D level may increase the risk for atherosclerotic cardiovascular disease. Whether a low vitamin D level plays a role in venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, is largely unexplored.

Carotid Intima-Media Thickness and Arterial Stiffness and the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, Multi-Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study.

BACKGROUND We evaluated the association of carotid intima-media thickness (cIMT), carotid plaque, carotid distensibility coefficient (DC), and aortic pulse wave velocity (PWV) with incident atrial fibrillation (AF) and their role in improving AF risk prediction beyond the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF risk score. METHODS AND RESULTS We analyzed data from 3 population-based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study (n=13 907); Multi-Ethnic Study of Atherosclerosis (MESA; n=6640), and the Rotterdam Study (RS; n=5220). We evaluated the association of arterial indices with incident AF and computed the C-statistic, category-based net reclassification improvement (NRI), and relative integrated discrimination improvement (IDI) of incorporating arterial indices into the CHARGE-AF risk score (age, race, height weight, systolic and diastolic blood pressure, antihypertensive medication use, smoking, diabetes, previous myocardial infarction, and previous heart failure). Higher cIMT (meta-analyzed hazard ratio [95% CI] per 1-SD increment, 1.12 [1.08-1.16]) and presence of carotid plaque (1.30 [1.19-1.42]) were associated with higher AF incidence after adjustment for CHARGE-AF risk-score variables. Lower DC and higher PWV were associated with higher AF incidence only after adjustment for the CHARGE-AF risk-score variables excepting height, weight, and systolic and diastolic blood pressure. Addition of cIMT or carotid plaque marginally improved CHARGE-AF score prediction as assessed by the relative IDI (estimates, 0.025-0.051), but not when assessed with the C-statistic and NRI. CONCLUSIONS Higher cIMT, presence of carotid plaque, and greater arterial stiffness are associated with higher AF incidence, indicating that atherosclerosis and arterial stiffness play a role in AF etiopathogenesis. However, arterial indices only modestly improve AF risk prediction.