The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis.

Educational inequalities in all-cause mortality have been observed for decades. However, the underlying biological mechanisms are not well known. We aimed to assess the role of DNA methylation changes in blood captured by epigenetic clocks in explaining these inequalities. Data were from 8 prospective population-based cohort studies, representing 13 021 participants. First, educational inequalities and their portion explained by Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, and DNAmGrimAge epigenetic clocks were assessed in each cohort via counterfactual-based mediation models, on both absolute (hazard difference) and relative (hazard ratio) scales, and by sex. Second, estimates from each cohort were pooled through a random effect meta-analysis model. Men with low education had excess mortality from all causes of 57 deaths per 10 000 person-years (95% confidence interval [CI]: 38, 76) compared with their more advantaged counterparts. For women, the excess mortality was 4 deaths per 10 000 person-years (95% CI: -11, 19). On the relative scale, educational inequalities corresponded to hazard ratios of 1.33 (95% CI: 1.12, 1.57) for men and 1.15 (95% CI: 0.96, 1.37) for women. DNAmGrimAge accounted for the largest proportion, approximately 50%, of the educational inequalities for men, while the proportion was negligible for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the World Health Organization (WHO) risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α.

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-α concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (ß [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (ß [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(ß [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (ß [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (ß [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (ß [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (ß [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5). Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.