DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5′-cytosine-phosphate-guanine-3′ (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes ( <jats:italic>AHRR</jats:italic> , <jats:italic>CPT1A</jats:italic> , <jats:italic>PPIF</jats:italic> , and <jats:italic>SBNO2</jats:italic> ) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk ( <jats:italic>P</jats:italic> ≤1.17×10 <jats:sup>−7</jats:sup> ). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index ( <jats:italic>P</jats:italic> ≤7.81×10 <jats:sup>−4</jats:sup> ). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16–1.51). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Age-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.</jats:p> </jats:sec>