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BACKGROUND: Although mounting evidence supports that aberrant DNA methylation occurs in the hearts of patients with atrial fibrillation (AF), noninvasive epigenetic characterization of AF has not yet been defined.METHODS: We investigated DNA methylome changes in peripheral blood CD4 T cells isolated from 10 patients with AF relative to 11 healthy subjects (HS) who were enrolled in the DIANA clinical trial (NCT04371809) via reduced-representation bisulfite sequencing (RRBS).RESULTS: An atrial-specific PPI network revealed 18 hub differentially methylated genes (DMGs), wherein ROC curve analysis revealed reasonable diagnostic performance of DNA methylation levels found within CDK5R1 (AUC = 0.76; p = 0.049), HSPG2 (AUC = 0.77; p = 0.038), WDFY3 (AUC = 0.78; p = 0.029), USP49 (AUC = 0.76; p = 0.049), GSE1 (AUC = 0.76; p = 0.049), AIFM1 (AUC = 0.76; p = 0.041), CDK5RAP2 (AUC = 0.81; p = 0.017), COL4A1 (AUC = 0.86; p < 0.001), SEPT8 (AUC = 0.90; p < 0.001), PFDN1 (AUC = 0.90; p < 0.01) and ACOT7 (AUC = 0.78; p = 0.032). 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.CONCLUSIONS: CDK5R1, GSE1, HSPG2 and WDFY3 resulted the best discriminatory genes both at methylation and gene expression level. Our results provide several candidate diagnostic biomarkers with the potential to advance precision medicine in AF.