Abstract 057: Epigenome Wide Association Study Identifies DNA Methylation Sites Associated With Target Organ Damage in Elderly African Americans

Introduction: Epigenetic mechanisms, including DNA methylation, influence gene expression and mediate responses to the environment over the lifecourse. Previous research has identified a number of DNA methylation sites (CpGs) associated with arteriosclerosis and its risk factors. Given the underlying role of immunological and inflammatory processes in arteriosclerosis and the potential of pleiotropic effects of individual CpG sites across organ systems influenced by arteriosclerosis, we investigated the DNA methylation profiles of peripheral blood leukocytes from a cohort of African American (AA) hypertensive sibships to explore their association with measures of target organ damage (TOD), analyzed using both single and multi-trait (multivariate) models. Methods: Using the Genome-wide Efficient Mixed Model Association algorithm (GEMMA), we assessed the association between ~790,000 CpGs across the genome and 4 TOD traits: Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI) and relative wall thickness (RWT) in 961 subjects with mean baseline age of 57.5 years (SD: 10.3). DNA methylation was measured at baseline using the Infinium MethylationEPIC BeadChip and TOD was assessed 5 years later. Results: Single trait models adjusting for age, sex, blood cell proportions, genetic principal components, and time difference between the measures identified a single CpG site associated with UACR (cg04816311), LVMI (cg21134922) and RWT (cg03042953, all FDR < 0.1). Pleiotropic (multivariate) models identified 8 CpGs associated with at least one of the traits in the CATSPERD, C7orf50, ALDH1L1, IFT43 and OAT genes. After adjusting for SBP, DBP and antihypertensive medication use, 6 CpGs remained significant and 1 additional CpG (cg21447579 in SNORD116 gene cluster) was identified. After further adjustment for BMI, T2DM and smoking, two CpGs (cg02264946 in CATSPERD and cg12661888 in IFT43) remained significant. Conclusions: The study highlights the role of specific epigenetic sites in risk of TOD in an African American population. Additionally, it highlights the utility of using a pleiotropy-based analysis to identify CpG sites by leveraging information across related traits.