Differentially Methylated DNA Regions and Left Ventricular Hypertrophy in African Americans: A HyperGEN Study

Abstract

Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and African Americans experience a disparate high risk of LVH. Genetic studies have identified potential candidate genes and variants related to the condition. Epigenetic modifications may continue to help unravel disease mechanisms. We used methylation and echocardiography data from 636 African Americans selected from the Hypertension Genetic Epidemiology Network (HyperGEN) to identify differentially methylated regions (DMRs) associated with LVH. DNA extracted from whole blood was assayed on Illumina Methyl450 arrays. We fit linear mixed models to examine associations between co-methylated regions and LV traits, and we then conducted single CpG analyses within significant DMRs. We identified associations between DMRs and ejection fraction (XKR6), LV internal diastolic dimension (TRAK1), LV mass index (GSE1, RPS15 A, PSMD7), and relative wall thickness (DNHD1). In single CpG analysis, CpG sites annotated to TRAK1 and DNHD1 were significant. These CpGs were not associated with LV traits in replication cohorts but the direction of effect for DNHD1 was consistent across cohorts. Of note, DNHD1, GSE1, and PSMD7 may contribute to cardiac structural function. Future studies should evaluate relationships between regional DNA methylation patterns and the development of LVH.

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“…DNA methylation at the candidate gene locus has been linked to the progression of hypertension 38 and hypertrophy, 39 supporting differences we observed in the hyper and hypomethylated DMR genes. In the context of the angiogenesis and CV-TOI, among the DMR genes, key genes are GSE1, for which differential methylation has been previously reported in patients with left ventricular hypertrophy and atrial fibrillation, 40,41 and VAV2, a guanine nucleotide exchange factor for Ras-related GTPases and modulate receptor-mediated angiogenic responses. Though there is no evidence for VAV2 methylation in blood pressure or cardiac diseases, it has been significantly associated with left ventricular hypertrophy, cardiac fibrosis, and hypertension.…”