<i>ABCA1, TCF7, NFATC1, PRKCZ,</i> and <i>PDGFA</i> DNA methylation as potential epigenetic-sensitive targets in acute coronary syndrome <i>via</i> network analysis

Acute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease. We performed an epigenome-wide analysis of circulating CD4⁺ and CD8⁺ T cells isolated from ACS patients and healthy subjects (HS), enrolled in the DIANA clinical trial, by reduced-representation bisulphite sequencing (RRBS). In CD4⁺ T cells, we identified 61 differentially methylated regions (DMRs) associated with 57 annotated genes (53% hyper- and 47% hypo-methylated) by comparing ACS patients <i>vs</i> HS. In CD8⁺ T cells, we identified 613 DMRs associated with 569 annotated genes (28% hyper- and 72% hypo-methylated) in ACS patients as compared to HS. In CD4⁺ <i>vs</i> CD8⁺ T cells of ACS patients we identified 175 statistically significant DMRs associated with 157 annotated genes (41% hyper- and 59% hypo-methylated). From pathway analyses, we selected six differentially methylated hub genes (<i>NFATC1, TCF7, PDGFA, PRKCB, PRKCZ, ABCA1</i>) and assessed their expression levels by q-RT-PCR. We found an up-regulation of selected genes in ACS patients <i>vs</i> HS (<i>P</i> ABCA1, TCF7, PDGFA, and <i>PRKCZ</i> gene expression was positively associated with CK-MB serum concentrations (<i>r</i> = 0.75, <i>P</i> = 0.03; <i>r</i> = 0.760, <i>P</i> = 0.029; <i>r</i> = 0.72, <i>P</i> = 0.044; <i>r</i> = 0.74, <i>P</i> = 0.035, respectively). This pilot study is the first single-base resolution map of DNA methylome by RRBS in CD4⁺ and CD8⁺ T cells and provides specific methylation signatures to clarify the role of aberrant methylation in ACS pathogenesis, thus supporting future research for novel epigenetic-sensitive biomarkers in the prevention and early diagnosis of this pathology.