Evaluation of Epigenetic Age Acceleration Scores and Their Associations with CVD-Related Phenotypes in a Population Cohort

SIMPLE SUMMARY: We consider a subset (n = 306) of an Eastern European ageing population cohort which was followed up for 15 years. Using blood DNA methylation data, we calculated nine epigenetic age acceleration scores, which are defined as deviations of epigenetic age from chronological age. We then evaluated how those scores are associated with available phenotypic data. This was implemented by splitting the phenotypic data into groups with positive and negative epigenetic age acceleration, and evaluating the difference between those groups. We observed strong association between all the considered epigenetic age acceleration and sex, suggesting that any analysis of these scores should be adjusted for sex. Moreover, even after adjusting for sex, the associations between the scores and considered phenotypes remain sex-specific. The only two associations that persisted through the entire dataset and both male and female subsets are incident coronary heart disease and smoking status. The observed associations of the various epigenetic age acceleration scores with both individual and groups of phenotypes suggest that these scores are sensitive to various cardiometabolic parameters, which might indicate their prognostic potential for related disorders. ABSTRACT: We evaluated associations between nine epigenetic age acceleration (EAA) scores and 18 cardiometabolic phenotypes using an Eastern European ageing population cohort richly annotated for a diverse set of phenotypes (subsample, n = 306; aged 45–69 years). This was implemented by splitting the data into groups with positive and negative EAAs. We observed strong association between all EAA scores and sex, suggesting that any analysis of EAAs should be adjusted by sex. We found that some sex-adjusted EAA scores were significantly associated with several phenotypes such as blood levels of gamma-glutamyl transferase and low-density lipoprotein, smoking status, annual alcohol consumption, multiple carotid plaques, and incident coronary heart disease status (not necessarily the same phenotypes for different EAAs). We demonstrated that even after adjusting EAAs for sex, EAA–phenotype associations remain sex-specific, which should be taken into account in any downstream analysis involving EAAs. The obtained results suggest that in some EAA–phenotype associations, negative EAA scores (i.e., epigenetic age below chronological age) indicated more harmful phenotype values, which is counterintuitive. Among all considered epigenetic clocks, GrimAge was significantly associated with more phenotypes than any other EA scores in this Russian sample.