Identification Of Hub Genes And Construction Of Proteinprotein Interaction (PPI) Network Clusters Define Racially Distinct Signatures Of Ischemic Heart Failure

Cardiovascular diseases, including ischemic heart failure (IHF), are the leading cause of mortality worldwide; furthermore, African Americans (AA) have 30% higher mortality than Caucasian Americans (CA). Our recent study correlates racial differences in socioeconomic status with DNA methylation (DNAm), altered gene expression, and mortality in HF independent of etiology. The current analysis focused on etiology-specific differences in DNAm with a specific focus on IHF, the related changes in gene expression, within self-reported race. RNA-seq expression ( P < 0.05, ±1.5-fold) and array-based methylation ( P < 0.05, ±5%) profiles were examined using cardiac biopsies from non-IHF (NIHF) and IHF AA (n = 9/5) and CA (n = 10/5) male patients. Network clusters were identified with MCODE (v2.0) and top hub genes identified via Cytohubba (v0.1). Both AA and CA patients showed similar numbers of IHF-specific differentially expressed genes (DEG) (591/365 AA; 439/486 CA; up/down). However, CA-specific methylation changes (29703/22703; up/down) were more abundant compared to AA (2904/2897; up/down). PPI network construction of these changes identified clusters unique to each group. The AA-specific upregulated cluster included AGPAT2, PPARG, and 10 other DEG associated with the fatty acid metabolism, while BMP2, SMAD6, and 4 other DEG that regulate BMP signaling and SMAD phosphorylation were downregulated. The CA-specific upregulated cluster included EZH2, CCNA1, and 18 other DEG that regulate mitotic sister chromatic separation, while EGFR, TNF, and 12 other DEG important for chronic inflammatory response formed the top downregulated cluster. Consistent with greater changes in DNAm the majority of DEGs in CA-specific clusters were also differentially methylated (58%) while fewer were in AA-specific clusters (17%). Within AA-specific PPI networks, PPARG/BMP2 (up/down) were the top ranked hub genes and KIF20A/KIT (up/down) in CA-specific networks. These racially distinct hub genes suggest altered regulatory mechanisms. Our analysis identified racially distinct clusters associated with specific pathways, which may connect the regulators of DNAm to gene expression and IHF, supporting the potential to use this information as prognostic biomarkers.