Epigenetic Determinants of Left Ventricular Structure and Function in Hypertensive African Americans

Left ventricular hypertrophy (LVH) is a condition affecting up to 43% of African Americans (AAs) and is an independent risk factor for cardiovascular (CV) endpoints. LVH is a determinant of CV death and nonfatal outcomes. LVH contributes more to the risk of CV mortality in AAs than it does in other race groups. Although effective treatments exist for other major CV risk factors (eg, hypertension), there is no treatment for LVH independent of behavioral or pharmacologic interventions for lowering blood pressure. It is widely accepted that genetic factors influence LV mass and other structural cardiac phenotypes. Heritability estimates have been as large as 0.59 for LV mass with higher heritability in AAs than Caucasians. This raises the question as to what genetic or epigenetic variants influence differences in LV phenotypes among race groups, and underscores the need to identify the variants. The Hypertension Genetic Epidemiology Network (HyperGEN) Genetics of LVH Study began in 1995 to explore the genetics of LVH in the context of hypertension. HyperGEN LVH collected echocardiographic measures in AAs using a standard protocol. HyperGEN has since identified genetic loci contributing to LVH and related traits through linkage, genome-wide association, and, currently, exome sequencing studies. The proposed study leverages the unique resource of hypertension-enriched families in HyperGEN with echocardiographic phenotypes and deep genomic information by incorporating whole-genome epigenetic analysis. Epigenetic processes such as DNA methylation underlie the gene-environment interactions in complex traits by changing gene expression. These changes are not encoded in the DNA sequence. We will implement an extreme sampling design to maximize phenotypic differences in HyperGEN, and we will validate our findings in extreme samples from other cohorts. Our study has three aims: In Aim 1 we will conduct whole-genome epigenetic analysis in 500 unrelated HyperGEN AAs with extreme high and low echocardiographic LV mass/height2.7 (hgt2.7) values to identify cytosine-phosphate-guanine (CpG) methylation sites contributing to LVH and other echocardiographic traits. In Aim 2, we will pyrosequence 5 CpGs detected in Aim 1 in 1000 AAs selected from extremes of LV mass/hgt2.7 in the Jackson Heart Study. In Aim 3, we will determine if significant CpGs in Aim 1 also demonstrate association in unrelated participants with LV mass/height2.7 values from the Framingham Heart Study.