Funding: National Heart, Lung, And Blood Institute, 2016-2020 (1 R01 HL 133221 01)
Arteriosclerosis (i.e., atherosclerosis and arteriolosclerosis) of the cardiac, cerebral, renal, and peripheral arteries leads to target organ damage and clinical sequelae such as heart attack, heart failure, stroke, dementia, chronic kidney disease, and claudication. Variations in a large number of genes have recently been identified that influence susceptibility to arteriosclerosis and target organ damage, but the influence of epigenetics on these same traits has not been extensively studied. The Genetic Epidemiology Network of Arteriopathy (GENOA) study was initiated in 1995 to study the genetics of hypertension and its target organ complications in sibships to optimize both linkage and association approaches to identifying genomic mechanisms underlying arteriosclerosis. Our preliminary studies in GENOA African Americans demonstrate relationships between genomic DNA methylation profiles (at ~27,000 markers genome-wide) measured in peripheral blood leukocytes and inter-individual differences in age, risk factors for arteriosclerosis, and target organ damage. In this application, we propose to use new and existing DNA methylation data (Aims 1-3) plus existing transcriptomic profiling (Aim 4) as cost-effective methods of identifying and studying the relationship between variation in DNA methylation across the genome and arteriosclerosis in GENOA African American sibships that are at high risk of developing various types of target organ damage from hypertension.