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DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women’s Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δage, at each timepoint. We fit linear mixed models to characterize how Δage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δage remained constant, indicating that age acceleration is generally stable over time. We found that Δage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.

Background: Exposure to traffic pollution during fetal development has been associated with reduced fetal growth, and there is evidence to suggest that epigenetic mechanisms in the placenta in the form of variant DNA methylation may be a potential mechanism underlying this effect. Objectives: To examine the association between residential proximity to nearest major roadway, as a marker of traffic-related pollution, fetal growth and placental DNA methylation. Methods: We obtained residential addresses, placenta samples, and demographic data from 471 women following delivery of term infants. Using generalized linear models we evaluated the association between living close to a major roadway (defined as living ≤150 m from a primary highway or primary road or ≤50 m from a secondary road) and fetal growth and DNA methylation of repetitive elements (LINE-1 and AluYb8). We evaluated epigenome-wide methylation in a subset of 215 women to further investigate specific variation in DNA methylation associated with proximity to major roadways. Results: Living close to a major roadway was associated with a 175.9 g (95% CI: −319.4, −32.5; p = 0.016) lower birth weight, 1.8 (95% CI: 0.9, 3.8; p = 0.09) times the odds of being small for gestational age, and 0.82 percentage points (95% CI: −1.57, −0.07; p = 0.03) lower mean placental LINE-1 methylation levels in fully adjusted models. In epigenome-wide analyses, 7 CpG sites were significantly associated with residential proximity to major roadways. Additional adjustment for placental methylation did not attenuate the association between roadway proximity and birth weight. Conclusions: Living close to major roadways was associated with both lower fetal growth and significant placental epigenetic changes. However, the observed epigenetic changes appear insufficient to explain the observed association between roadway proximity and fetal growth. Keywords: Traffic, Pollution, Epigenetics, Placenta, Birth weight

Background: With the emergence of obesity as a global health issue, an increasing number of major demographic surveys are collecting measured anthropometric data. Yet little is known about the characteristics and reliability of these data. Objective: We evaluate the accuracy and reliability of anthropometric data collected in the home during Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health), compare our estimates to national standard, clinic-based estimates from the National Health and Nutrition Examination Survey (NHANES) and, using both sources, provide a detailed anthropometric description of young adults in the United States. Methods: The reliability of Add Health in-home anthropometric measures was estimated from repeat examinations of a random subsample of study participants. A digit preference analysis evaluated the quality of anthropometric data recorded by field interviewers. The adjusted odds of obesity and central obesity in Add Health vs. NHANES were estimated with logistic regression. Results: Short-term reliabilities of in-home measures of height, weight, waist and arm circumference - as well as derived body mass index (BMI, kg/m2) - were excellent. Prevalence of obesity (37Š vs. 29Š) and central obesity (47Š vs. 38Š) was higher in Add Health than in NHANES, while socio-demographic patterns of obesity and central obesity were comparable in the two studies. Conclusions: Properly trained non-medical field interviewers can collect reliable anthropometric data in a nationwide, home visit study. This national cohort of young adults in the United States faces a high risk of early-onset chronic disease and premature mortality.

Background Repolarization abnormality in bundle branch blocks (BBB) is traditionally ignored. This study evaluated the prognostic value of QRS/T angle for mortality in the presence and absence of BBB. Methods and results Total 15,408 participants (mean age 54 years, 55.2% women, 26.9% blacks, 2.8% with BBB) were from the Arteriosclerosis Risk in Communities Study. Sex stratified Cox regression models were used to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for coronary heart disease (CHD) and all-cause mortality for wide spatial QRS/T angle with and without BBB including right BBB (RBBB), left BBB (LBBB) and indetermined-type ventricular conduction defect (IVCD) and RBBB combined with left anterior fascicular block. During a median 22-year follow-up, 4767 deaths occurred, 728 of them CHD deaths. Using the No-BBB with QRS/T angle below median value as gender-specific reference groups, the mortality risk increase was significant for both women and men with No-BBB and QRS/T angle above the median value. In the pooled ICVD/LBBB group, the risk for CHD death was increased 15.9-fold in women and 6.04 fold in men, and for all-cause deaths 3.01-fold in women and 1.84-fold in men. However, the mortality risk in isolated RBBB group was only significantly increased in women but not in men. Conclusion A wide spatial QRS/T angle in BBB is associated with increased risk for CHD and all-cause mortality over and above the predictive value for BBB alone. The risk for women is as high as or higher than that in men.

Studies have reported relationships between urban sprawl, physical activity, and obesity, but - to date - no studies have considered the relationship between sprawl and coronary heart disease (CHD) endpoints. In this analysis, we use longitudinal data on post-menopausal women from the Women's Health Initiative (WHI) Clinical Trial to analyze the relationship between metropolitan statistical area (MSA)-level urban compactness (the opposite of sprawl) and CHD endpoints including death, any CHD event, and myocardial infarction. Models control for individual and neighborhood socio-demographic characteristics. Women who lived in more compact communities at baseline had a lower probability of experiencing a CHD event and CHD death or MI during the study follow-up period. One component of compactness, high residential density, had a particularly noteworthy effect on outcomes. Finally, exploratory analyses showed evidence that the effects of compactness were moderated by race and region.

Background: This paper presents an application of quantitative ion character–activity relationships (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties. Objectives: The objective of this work was to examine potential associations of biological end points with a set of physical and chemical properties describing inorganic metal ions present in exposures using QICAR. Methods: Chemical and physical properties of 17 metal ions were obtained from peer-reviewed publications. Associations of cardiac arrhythmia, myocardial ischemia, myocardial infarction, stroke, and thrombosis with exposures to metal ions (measured as inference scores) were obtained from the Comparative Toxicogenomics Database (CTD). Robust regressions were applied to estimate the associations of CVDs with ion properties. Results: CVD was statistically significantly associated (Bonferroni-adjusted significance level of 0.003) with many ion properties reflecting ion size, solubility, oxidation potential, and abilities to form covalent and ionic bonds. The properties are relevant for reactive oxygen species (ROS) generation, which has been identified as a possible mechanism leading to CVDs. Conclusion: QICAR has the potential to complement existing epidemiologic methods for estimating associations between CVDs and air pollutant exposures by providing clues about the underlying mechanisms that may explain these associations.

Background— Knowledge of trends in the incidence of and survival after myocardial infarction (MI) in a community setting is important to understanding trends in coronary heart disease (CHD) mortality rates. Methods and Results— We estimated race- and gender-specific trends in the incidence of hospitalized MI, case fatality, and CHD mortality from community-wide surveillance and validation of hospital discharges and of in- and out-of-hospital deaths among 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities (ARIC) Study. Biomarker adjustment accounted for change from reliance on cardiac enzymes to widespread use of troponin measurements over time. During 1987–2008, a total of 30 985 fatal or nonfatal hospitalized acute MI events occurred. Rates of CHD death among persons without a history of MI fell an average 4.7%/y among men and 4.3%/y among women. Rates of both in- and out-of-hospital CHD death declined significantly throughout the period. Age- and biomarker-adjusted average annual rate of incident MI decreased 4.3% among white men, 3.8% among white women, 3.4% among black women, and 1.5% among black men. Declines in CHD mortality and MI incidence were greater in the second decade (1997–2008). Failure to account for biomarker shift would have masked declines in incidence, particularly among blacks. Age-adjusted 28-day case fatality after hospitalized MI declined 3.5%/y among white men, 3.6%/y among black men, 3.0%/y among white women, and 2.6%/y among black women. Conclusions— Although these findings from 4 communities may not be directly generalizable to blacks and whites in the entire United States, we observed significant declines in MI incidence, primarily as a result of downward trends in rates between 1997 and 2008.

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10−4): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10−5): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation., Author Summary The QT interval (QT) provides a measure of a ventricular action potential, and its prolongation is associated with sudden death and ventricular arrhythmias. Genome-wide association studies performed in European populations have identified common genetic variants that influence QT. However, it is unclear whether these variants are relevant in other populations, including African Americans. The increased genetic diversity in African Americans also provides opportunities to narrow association signals and identify candidates for functional evaluation. We therefore used data from 8,644 African Americans to further characterize previously identified QT loci. Of the fifteen known independent QT variants at the eleven previously identified QT loci, six were associated with QT in African Americans. We also identified three variants that were independent from previously reported signals and narrowed intervals flanking association signals using patterns of linkage disequilibrium. Finally, bioinformatic-based characterization pointed to candidates located outside protein coding regions. Our results underscore the utility of genetic studies in African ancestral populations to identify novel variants and narrow intervals surrounding established loci. These results suggest that known QT loci are important in African Americans and that further characterization of these loci in other populations may provide additional insights into the genetic and molecular mechanisms underlying QT.

Issues surrounding choice of time scales in Cox proportional hazard regression models have received limited attention in the literature. Although the choice between time on study and ‘attained’ age time scales has been examined, the calendar time scale may be of interest when modeling health effects of environmental exposures with noteworthy secular trends such as ambient particulate matter air pollution in large epidemiological cohort studies. The authors use simulation studies to examine performance (bias, mean squared error, coverage probabilities, and power) of models using all three time scales when the primary exposure of interest depends on calendar time. Results show that performance of models fit to the calendar time scale varies inversely with the strength of the linear association between the time-varying primary exposure and calendar time. Although models fit to attained age and time on study that do not adjust for calendar time were relatively robust, the authors conclude that care should be exercised when using time scales that are highly correlated with exposures of interest.

Purpose Racial and gender disparities in out-of-hospital deaths from coronary heart disease (CHD) have been well-documented, yet disparities by neighborhood socioeconomic status (nSES) have been less systematically studied in US population-based surveillance efforts. Methods We examined the association of nSES, classified into tertiles, with 3,743 out-of-hospital fatal CHD events, and a subset of 2,191 events classified as sudden, among persons aged 35 to 74 years in four US communities under surveillance by the Atherosclerosis Risk in Communities (ARIC). Poisson generalized linear mixed models generated age-, race- (white, black) and gender-specific standardized mortality rate ratios and 95% confidence intervals (RR, 95% CI). Results Regardless of nSES measure used, inverse associations of nSES with all out-of-hospital fatal CHD and sudden fatal CHD were seen in all race-gender groups. The magnitude of these associations was larger among women than men. Further, among blacks, associations of low nSES (vs. high nSES) were stronger for sudden cardiac deaths (SCD) than for all out-of-hospital fatal CHD. Conclusions Low nSES was associated with an increased risk of out-of-hospital CHD death and SCD. Measures of the neighborhood context are useful tools in population-based surveillance efforts for documenting and monitoring socioeconomic disparities in mortality over time.