DNA methylation biomarkers of myocardial infarction and cardiovascular disease

Abstract

Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identifed biomarkers is still limited. We aimed to identify diferentially methylated loci associ‑ ated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infnium MethylationEPIC BeadChip. We performed a fxed efects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n~1800 and n~2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infnium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic infuence and therefore the results were not conclusive. Conclusions: We have identifed 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metab‑ olism, and infammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information