DNA methylation predicts adverse outcomes of coronary artery disease.

Adverse outcomes including myocardial infarction (MI) and stroke render coronary artery disease (CAD) a leading cause of death worldwide. DNA methylation markers may alert such adversity ahead of the events. We profiled DNA methylation of blood leukocytes in 933 Chinese CAD patients with up-to-13-year follow-up from three centers, identifying 70 differentially methylated sites (DMPs) associated with future death. These DMPs correlated with inflammation markers, left ventricular functions and high-density lipoprotein cholesterol, and impacted gene expression in immune response and cellular scenesence. Notably, cg25563198 and cg25114611 were discovered to regulate FKBP5, whose upregulation persisted during MI and stroke. Fkbp5 knockout in male mice partially rescued MI by reducing infarct size and improving heart function, confirming its critical function. Finally, our prognostic model of 10 methylation sites and 5 clinical features outperformed clinical models. Our study highlights the value of DNA methylation in predicting prognosis in CAD and provides tools for clinical translation.