Epigenetic modifications have emerged as potential contributors to atherosclerotic cardiovascular disease and may offer insights into disease mechanisms and risk stratification. A study published in the Journal of the American College of Cardiology evaluated DNA methylation patterns associated with carotid, coronary, and peripheral atherosclerosis and assessed the extent to which these signatures reflected established cardiovascular risk factors.

The analysis included 3,688 participants from two prospective cohort studies. Blood DNA methylation was assessed at 767,735 CpG sites, epigenome-wide association studies were performed for multiple atherosclerosis phenotypes. Methylation scores were subsequently evaluated for their discriminatory and prognostic performance. 

Findings

• A total of 1,687 CpG sites were associated with carotid atherosclerosis, 3,131 with coronary atherosclerosis, and 5,852 with peripheral atherosclerosis.
• Strong associations across phenotypes mapped to loci near ALPP/ALPG, AHRR, PRSS23, and F2RL3, with additional prominent signals involving ABCG1 and DHCR24 in  coronary atherosclerosis.
• Epigenetic scores were associated with future 3-point major adverse cerebrovascular and cardiovascular events, with hazard ratios ranging from 1.23 to 1.39 (all P<0.001).
• More than 90% of atherosclerosis-associated CpG sites overlapped with cardiovascular risk factor–associated sites, particularly smoking-related methylation signatures.

Adjustment for smoking pack-years reduced methylation effect estimates by 19.6% to 29.0%, while joint adjustment for all cardiovascular risk factor markers reduced estimates by 25.5% to 32.8%.