African Americans (AAs) are at an increased risk for high blood pressure (BP), chronic kidney disease (CKD), and left ventricular hypertrophy (LVH) compared to other US populations, which leads to increased risk for cardiovascular disease and stroke. The observed disparities in these cardiorenal traits are both genetic and environmental in origin. Despite data showing that the heritability of cardiorenal traits is higher in AAs compared to other populations, most of the predisposing genetic factors remain unknown. Additionally, the role of epigenetic mechanisms such as DNA methylation, which synthesizes inputs from both the genome and the environment, in determining the cardiorenal risk profile has not been comprehensively investigated in diverse populations. To address these gaps, we propose a study of genetic and epigenetic determinants of cardiorenal traits in three population-based AA cohorts (Hypertension Genetic Epidemiology Network, Genetic Epidemiology Network of Arteriopathy, and Jackson Heart Study; total n=6,500). We have existing whole genome sequencing data that offers unprecedented resolution at 30x coverage as well as DNA methylation data in all three cohorts, and we plan to analyze it on a genome-wide scale using cutting-edge statistical methods implemented in the AHA Precision Medicine Platform. Furthermore, we will interrogate the functional relevance of our top findings by using existing gene expression data in blood (n=1,238) and induced pluripotent stem cell-derived cardiomyocytes (n=100), the latter particularly relevant to understanding cardiovascular sequelae of cardiorenal dysfunction and not available in other AA cohorts. Finally, we will analytically integrate our uniquely detailed genomic, epigenomic, and gene expression data layers to produce novel insights into the pathogenesis of cardiorenal disease in AAs. Successful completion of our aims will identify genomic regions of particular importance to cardiovascular and renal health in the AA population, informing future efforts to develop more precise and effective treatment and screening strategies, as well as create a scalable and interoperable analytic pipeline that can be further adapted to other cardiovascular phenotypes, advancing the AHA's missions of 1) democratizing precision medicine and 2) promoting equity in health research and outcomes.
|Program type||Institute - Democratizing Data|
|Effective start/end date||07/01/2018 → 06/30/2020|