2 Circ Genom Precis Med. 2018; 11: e002089. DOI: 10.1161/CIRCGEN. 118.002089 March 2018 age predictors were moderately correlated with each other (r= 0.6), and there was a spread of 8 to 9 years in epigenetic age acceleration or deceleration across the cohort participants. Incident CVD outcomes, assessed by annual surveillance, hospital record diagnosis codes, and validated by physician review, included probable or definite myocardial infarction, fatal coronary heart disease event, peripheral artery disease, heart failure, and CVD mortality. Subclinical atherosclerosis, assessed by ultrasound imaging of carotid intima-media thickness, was studied in relation to concurrent epigenetic age acceleration measures.

The investigators demonstrated that both epigenetic age acceleration measures are associated with classic CVD risk factors at baseline, such as male sex, smoking, and diabetes mellitus. Each of those factors is related with an epigenetic age that is 1 to 2 years older than chronological age. At baseline, epigenetic age acceleration is associated with carotid intima-media thickness after adjusting for chronological age, sex, education, health behaviors (smoking, alcohol intake, sports index), body mass index, diabetes mellitus, systolic blood pressure, use of antihypertensive medications, total cholesterol, high-density lipoprotein cholesterol, use of cholesterol-lowering medications, self-rated health status, cell count, and methylation technical and batch covariates; demonstrating≈ 0.01 mm thicker carotid intima-media thickness per 5-year increment in epigenetic age acceleration. Participants were found to be at a 10% to 20% increased risk for most of the CVD outcomes per each 5-year increase in epigenetic age acceleration in similar multivariable-adjusted models. Unsurprisingly, the magnitude of the association with carotid intima-media thickness and incident CVD events is smaller for epigenetic age acceleration than that observed for the same increment in years of chronological age. However, the regression coefficients are closer than what may have originally been expected. For example, the strongest relationship is for fatal coronary heart disease events with hazard ratios per 5-year increase in epigenetic age acceleration of 1.17 (95% confidence interval, 1.02–1.33) and 1.22 (95% confidence interval, 1.04–1.44) for the Horvath and Hannum predictors, respectively; which is around half the magnitude as observed for chronological age (hazard ratio, 1.35;[95% confidence interval, 1.15–1.59]). Despite being assembled from less CpGs (71 versus 353), the epigenetic age acceleration based on the Hannum markers, which was derived from whole blood samples, is more strongly linked to CVD outcomes than the epigenetic age acceleration based on the Horvath markers, which were derived in multiple cells and tissues; likely because of the current study sample using DNA derived from whole blood leukocytes. Although there is no internal or external replication, the findings are consistent with previous reports from meta-analyses