Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans

Abstract

Background Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention. Results Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22–2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040–0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006–0.064). Conclusions Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.

Epigenetic age acceleration and cardiovascular outcomes in school-age children: The Generation R Study

“…Both an American and a Scottish study among 969 and 5100 adults, respectively, reported that positive age acceleration as estimated by the clock of Hannum, but not that of Horvath, was associated with hypertension [ 26 , 28 ]. A study among 1100 mostly hypertensive African-Americans reported that positive age acceleration was associated with blood pressure, using Horvath’s and Hannum’s clocks [ 27 ]. In addition, this study, as well as two studies among 4178 women from the Women’s Health Initiative, only reported associations with systolic but not diastolic blood pressure when using the PhenoAge and GrimAge clocks [ 27 , 31 , 32 ].…”

Methylation of FKBP5 is associated with accelerated DNA methylation ageing and cardiometabolic risk: replication in young-adult and middle-aged Black Americans

“…Building on prior theorizing [41], we tested a model in which demethylation of the two CpG sites on FKBP5 previously shown to be demethylated in response to stress and ageing, set in motion a broader set of biological changes captured by indices of accelerated ageing and ultimately lead to elevated risk for cardiometabolic illness [47]. In keeping with Levine et al (2018) [26], and more recently Ammous et al (2021) [30], we proposed that currently available DNA methylation-based indices of intrinsic accelerated ageing would potentially capture the impact of FKBP5-2 demethylation on a range of biological systems, and so constitute an intermediate step in the progression to elevated cardiometabolic risk (i.e., elevated blood pressure, elevated HbA1c, blood sugar, inflammation, BMI). These considerations led to our expectation that there would be a significant association of FKBP5-2 with accelerated ageing (AA), significant indirect effects from FKBP5-2 to two measures of cardiometabolic risk (CMR and FCMR10), and that similar patterns of association would be observed across the lifespan for both outcomes, using intrinsic measures of AA.…”

“…If methylation of these two FKBP5 loci are a reflection of biological embedding of early risk [35][36][37][38]58,59], and continue to exert an influence across the lifespan, we would expect to observe associations between their methylation levels and DNA methylation-based indices of accelerated ageing, which in turn would lead to elevated CMR (e.g [30]. Ammous et al, 2021).…”

“…If methylation of these two FKBP5 loci are a reflection of biological embedding of early risk [35][36][37][38]58,59], and continue to exert an influence across the lifespan, we would expect to observe associations between their methylation levels and DNA methylation-based indices of accelerated ageing, which in turn would lead to elevated CMR (e.g [30]. Ammous et al, 2021). Such effects could also be expected to influence DNAmethylation-based indices of accelerated ageing using measures derived from whole blood, and to exert long-term effects on increased risk for CMR observable for both younger and older cohorts.…”

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

“…Epigenetics plays a major role in the occurrence and progression of several CVDs, such as cardiac hypertrophy, heart failure, ischemic heart disease, aortic aneurysm, vascular calcification, and pulmonary hypertension, by mediating gene expression and cellular function (13). Furthermore, epigenetics implies the heritable alteration in the gene expression landscape without alterations in DNA sequence caused by the changes in nucleosome remodeling, which represents the architecture of chromatin and regulates the accessibility of DNA (14). The altered nucleosome remodeling is attributed to the interaction between the environment and the genome (15).…”