DNA hypermethylation of MED1 and MED23 as early diagnostic biomarkers for unsolved issues in atrial fibrillation

Although evidence supports that aberrant DNA methylation exists in the hearts of patients with atrial fibrillation (AF), epigenetic phenomena underlying the onset and progression of AF are not yet fully understood. We therefore investigated DNA methylome changes in circulating CD4+ T cells isolated from AF patients and healthy subjects (HS), enrolled in the ongoing DIANA clinical trial (NCT04371809), by using reduced-representation bisulfite sequencing (RRBS). Network analysis was applied to investigate differential DNA methylation profiles and functional effects. An atrial-specific PPI network revealed 18 hub differentially methylated genes (DMGs). ROC curve analysis revealed that DNA methylation levels of CDK5R1 (AUC = 0.755; P = 0.049), HSPG2 (AUC = 0.768; P = 0.038), WDFY3 (AUC = 0.782; P = 0.029), USP49 (AUC = 0.755; P = 0.049) and GSE1 (AUC = 0.755; P = 0.049), AIFM1 (AUC = 0.764; P = 0.041), CDK5RAP2 (AUC = 0.809; P = 0.017), COL4A1 (AUC = 0.864; P<0.001), SEPT8 (AUC = 0.900; P<0.001), PFDN1 (AUC = 0.900; P<0.01), and ACOT7 (AUC = 0.777; P = 0.032) provided a good performance on predicting the presence AF. Transcriptional profiling of the hub DMGs provided a significant overexpression of PSDM6 (P=0.004), TFRC (P=0.01), CDK5R1 (P<0.001), HSPG2 (P=0.01), WDFY3 (P<0.001), USP49 (P=0.004), and GSE1 (P=0.021) in AF patients vs HS. CDK5R1, GSE1, HSPG2, and WDFY3 resulted the best discriminatory genes both at methylation and gene expression level. Our results provide putative diagnostic biomarkers with the potential to advance precision medicine in AF. Overall design: Peripheral blood was collected from patients with a diagnosis of atrial fibrillation or no known diagnosis of cardiac dysrhythmia.