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BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Much effort was spent to identify biomarkers useful to stratify AF patients. Mediator complex (MED) is an ancestral regulator of transcriptional mechanisms. Here, we investigated the role of methyl DNA-MED regulatory networks in AF patients.METHODS: We analyzed the methylome of circulating CD4T lymphocytes isolated from patients at the time of first AF diagnosis vs. healthy subjects for identifying epigenetic dysregulation of MED-related genes.RESULTS: We identified 10 differentially methylated regions (DMRs) which were hypermethylated and annotated to 10 genes encoding for MED complex subunits in CD4T lymphocytes of AF patients vs. healthy subjects (HS). Network-oriented analysis prioritized 6 subunits including MED1, MED13, MED15, MED17, MED23 and MED30, which enriched significantly lipid metabolism pathways and cardiopathy onset. ROC curve analysis showed that elevated methylation levels of MED1 and MED23 discriminated AF patients with an area under the curve (AUC) of 92.7 % (p < 0.001) and an AUC = 100 % (p < 0.001), respectively. Methylation levels of MED23 correlated with the presence of mitral valve disease (p < 0.05) and NT-proBNP (p < 0.05); moreover, MED23 had a not inferior diagnostic value than circulating levels of NT-proBNP (AUC = 0.923, p < 0.001).CONCLUSIONS: For the first time, we showed that DNA methylation changes are associated with regulation of MED complex subunits in early diagnosis of AF patients. Clinically, MED1 and MED23 hypermethylation showed a diagnostic value not inferior to circulating levels of NT-proBNP suggesting early diagnostic biomarker pathogenic molecular routes underlying disease onset.