Abstract 10692: Combined Methylomics and Transcriptomics Identifies a Race-Specific Signature of Ischemic Heart Failure in Atrial Natriuretic Peptide Gene Regulation

Abstract

African Americans (AA) face a greater burden of cardiovascular diseases, including ischemic cardiomyopathy (ICM), compared to Caucasian Americans (CA). Our recent work supports that epigenetics is likely a unifying mechanism between health disparities of socioeconomic inequalities and heart failure severity; whereby environmental factors are incorporated as stable DNA modifications to confer susceptibility to heart failure. We hypothesized that ICM possesses racially distinct methylome signatures. Cardiac biopsies from male age- and disease-matched AA (n = 14) and CA (n = 15) heart failure patients with ICM and non-ICM (NICM) were subjected to expression analysis using RNA-seq ( P < 0.05, ±1.5-fold) and differential methylation analysis using Illumina EPIC array ( P < 0.05, ±5%) using generalized linear models with a focus on changes corresponding to ICM and racial differences. Comparing ICM vs NICM, both AA and CA patients showed racially distinct differentially expressed genes (594/366 within AA; 439/487 within CA; up/down respectively). Similarly, pathway analysis using the NIH’s BioPlanet database found a significant change ( Q < 0.1) in AA for adipogenesis (25/133 overlap) and in CA for complement cascade (18/77 overlap). In contrast, racially distinct DNA methylation changes were more prominent for CA (29703/22703; up/down) compared to AA (2904/2897; up/down). Upon combining both datasets, known heart failure marker NPPA , which encodes Atrial Natriuretic Peptide, was found to be downregulated in ICM compared to NICM only for AA ( Q = 0, 18.9-fold change), corresponding to hypermethylation of 6 CpG sites ( P < 0.05, 6.4 - 11.3%). NPPA inhibits cardiac hypertrophy, fibrosis, and decreases inflammation. It is also used as a diagnostic biomarker in ICM. But recent trials found that AA have lower levels of NPPA in blood compared to CA, even in healthy condition. This patient cohort also indicated a racially diverse pattern of NPPA expression and methylation. Given its role in adipogenesis, NPPA may also explain the pathway enrichment specific to AA-ICM patients. Our data indicate that NPPA may connect the socioeconomic effects through DNA methylation with clinical diversity of ICM. It also underscores the need for a better prognostic biomarker for ICM.