Abstract MP25: Adiposity-related DNA Methylation as a Predictor of Coronary Heart Disease in Adult African Americans: The Atherosclerosis Risk in Communities Study

Abstract

Background: Epigenetic modifications such DNA methylation variation comprise a potentially useful new class of biomarkers that may improve coronary heart disease (CHD) risk stratification, or better capture early pathophysiological processes. However, replicated associations of DNA methylation and CHD are few, and existing studies are primarily cross-sectional and restricted to European ancestry populations. Given the strong association of excess adiposity with CHD risk, we tested 41 DNA methylation variants (CpG sites) that were previously reported to be associated with BMI in African Americans (AA), and tested their association with incident CHD in AA adults. Methods: Genome-wide DNA methylation variation was assayed at a single time point in stored frozen leukocyte samples using the Illumina HM450K chip in a subset of 1,797 AA participants in the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study of cardiovascular disease risk conducted in four U.S. communities. Methylation beta values and other continuous covariates were winsorized prior to analysis to reduce outlier influence. Incident CHD cases were identified through annual telephone interviews and medical records review. Proportional hazards regression (frailty) models examined the relationship between DNA methylation beta values and incident CHD with separate models for each of the 41 CpGs, with a random effect specified for chip. Fully adjusted models included age, BMI, sex, center, education, household income, leisure time activity, alcohol and tobacco use, white blood cell count and imputed cell type differentials. To explore the relationship between DNA methylation and CHD risk accounting for major CHD risk factors, mediator models additionally contained prevalent hypertension status, blood glucose, and total and HDL cholesterol. A Bonferroni-corrected p value of 0.00122 was set as the threshold for statistical significance. Results: There were 224 cases of incident CHD out of 1,797 individuals at risk. One CpG, cg09664445 near CLUH was significantly associated with incident CHD in the full (HR=1.47, 95%CI=1.26, 1.72) and mediator model (HR=1.46, 95% CI=1.24, 1.71) while cg06500161 near ABCG1 was significant in the full model only (HR=1.34, 95% CI=1.15, 1.56). Conclusion: Two obesity-related DNA methylation variants were associated with incident CHD independent of known risk factors and potential confounders. In the literature, CLUH is involved in mitochondrial biogenesis while promoter hypermethylation of ABCG1 was previously found to increase CHD risk and atherosclerosis. Replication in additional cohorts is required to further investigate the predictive value of DNA methylation variants over established risk factors and biomarkers for CHD.