Genome-wide DNA methylation profiling in blood reveals epigenetic signature of incident acute coronary syndrome

DNA methylation (DNAm) has been implicated in acute coronary syndrome (ACS), but the causality remains unclear in cross-sectional studies. Here, we conduct a prospective epigenome-wide association study of incident ACS in two Chinese cohorts (discovery: 751 nested case-control pairs; replication: 476 nested case-control pairs). We identified and validated 26 differentially methylated positions (DMPs, false discovery rate [FDR] <0.05), including three mapped to known cardiovascular disease genes (PRKCZ, PRDM16, EHBP1L1) and four with causal evidence from Mendelian randomization (PRKCZ, TRIM27, EMC2, EHBP1L1). Two hypomethylated DMPs were negatively correlated with the expression in blood of their mapped genes (PIGG and EHBP1L1), which were further found to overexpress in leukocytes and/or atheroma plaques. Finally, our DMPs could substantially improve the prediction of ACS over traditional risk factors and polygenic scores. These findings demonstrate the importance of DNAm in the pathogenesis of ACS and highlight DNAm as potential predictive biomarkers and treatment targets.