Abstract 4147025: Obesity as an Underlying Driver of Differences in Racial and Socioeconomic Disparity Associated Cardiac DNA Methylation Among Men with End-stage Heart Failure

Heart failure (HF) treatment advances have improved outcomes but HF heterogeneity leads to ~50% response to standard therapies, emphasizing a need to further study mechanisms of disparate outcomes. One serious disparity is increased cardiovascular disease risk and mortality in African Americans (AA) compared to Caucasian Americans (CA). Race is a social construct and thus poor proxy for physiology; hence, our lab studies epigenetics, stable yet reversible changes to DNA serving as a possible interface of how environment impacts gene regulation. We’ve previously implicated cardiac DNA methylation as a new indicator of socio-economic disparities in HF outcomes. Related to HF, US adult obesity rates are 40% and similar disparities exist with AA having higher rates, and studies on obesity show how inequity leads to disparate rates. Thus, our secondary analysis investigates the role of obesity, through its impact on cardiac epigenetics and transcription, as an underlying environment/molecular driver within HF disparities. Multi-omics data of left ventricular assist device placement biopsies of age-matched males were from our previous publication’s public dataset. Cardiac DNA methylation (850k-array) analyzed via minfi, and differential gene expression (RNA-seq) via DESeq2. Two-year survival is decreased in non-obese (NO) vs. obese (OB) patients (p<0.01); specifically, decreased survival in AA-NO patients vs. CA-NO patients (Hazard Ratio=0.26, 0.08-0.91). Subgroup analyses reveal 2632 gene-associated differentially methylated CpG-probes between AA-NO vs. OB, and 5309 between CA-NO vs. OB (p<0.05, |methyl-change|>5%). Additionally, 19 differentially expressed genes between AA-NO vs. OB, and 236 between CA-NO vs. OB (q<0.1, |Log FC|>1.5); one key gene, TNFa induced protein 8 ( TNFAIP8 ), is increased in AA-NO vs. OB, but decreased in CA-NO vs. OB. Furthermore, the differential expression in each group correlates with canonical significant inverse DNA methylation at TNFAIP8 . Our survival data supports the literature of an “Obesity Paradox” where obese HF patients have better prognoses than non-obese patients. Through our analyses, we characterized impacts of obesity status on DNA methylation and gene expression within disparate HF outcomes and identified TNFAIP8 as a marker related to increased apoptosis in pathology progression. Thus, our work contributes molecular characterization of a possible effector of the differences seen in these specific patient populations.