Effects of DNA Methylation on Cardiovascular Disease, Target Organ Damage, and their Risk Factors in African Americans

Cardiovascular disease (CVD) is the leading cause of mortality among US adults, and African Americans have a higher burden of CVD morbidity and mortality than any other racial group. Identification of novel CVD biomarkers is essential to better identify at-risk individuals, advance precision medicine, and inform efforts to reduce CVD burden. DNA methylation (DNAm) is an epigenetic mechanism that captures genetic influences as well as imprints of lifestyle and environmental exposures throughout the life course. DNAm patterns may help identify biological mechanisms contributing to CVD pathogenesis. This dissertation explores the effects of DNAm and DNAm-based epigenetic age acceleration (EAA) on cardiometabolic risk factors, atherosclerosis, CVD incidence, and target organ damage from hypertension (TOD) in African American participants from the Genetic Epidemiology Network of Arteriopathy (GENOA). In Aim 1, we used univariate and multivariate linear mixed models to assess the epigenome-wide association between DNAm sites (CpGs) and measures of TOD in the heart (left ventricular mass index (LVMI) and relative wall thickness (RWT)), kidneys (estimated glomerular filtration rate (eGFR) and albuminuria), and brain (white matter hyperintensity). LVMI, RWT, and albuminuria were each associated with one CpG in univariate models, and seven CpGs were associated with TOD measures in the multivariate (pleiotropy) model (false discovery rate (FDR) 0.05), and marginally improved net reclassification index (NRI) which assesses reassignment of risk categories (NRI = 0.055, 95% CI: 0.040 – 0.071 for FRS; 0.029, 95% CI: 0.006 – 0.064 for ASCVD). In Aim 3, we evaluated in prospective analyses whether EAA measures, previously identified atherosclerosis-associated CpGs, and methylation risk scores (MRSs) derived from these CpGs are associated with single- or multi-site atherosclerosis (coronary artery calcification (CAC), abdominal aorta calcification (AAC), and ankle-brachial index (ABI)). One and six CpGs were associated with AAC and multi-site atherosclerosis, respectively (FDR < 0.1). Both a 5-year increase in GrimAA as well as a one unit increase in the MRS for carotid artery plaque were associated with a 1.6-fold increase in AAC and 0.7 units increase in multi-site atherosclerosis (score range: 0-12) after adjusting for CVD risk factors (Bonferroni-adjusted P < 0.05). Together, these studies support the premise that DNAm plays an important role in CVD and TOD and is a promising biomarker that may improve risk assessment in African Americans.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167983/1/fammous_1.pd