An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease

Abstract

BackgroundEpigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.ConclusionsEpigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1030-0) contains supplementary material, which is available to authorized users.

Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

“…In comparison, DNAm Δage was previously shown to be associated with all‐cause mortality, but not with prevalent CHD or hypertension (Marioni et al ., 2015; Horvath et al ., 2016). mRNA Δage was reported to be associated with blood pressure, glucose, and HDL and total cholesterol, but not with all‐cause mortality (Peters et al ., 2015).…”

“…The resultant DNA methylation‐based predicted age ( i.e ., DNAm age) was associated with chronological age in several independent studies. The difference between DNAm age and chronological age ( i.e ., DNAm Δage) has been proposed as an index of accelerated aging and was reported to be associated with all‐cause mortality and several coronary heart disease risk factors (Marioni et al ., 2015; Christiansen et al ., 2016; Horvath et al ., 2016). …”

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

“…For example, aging is a crucial risk factor for cancer [72,73] and also relevant to the treatment outcome [74]. Studies have shown that the epigenetic age of human tissues can be defined by the methylation level of 353 CpG sites, which are termed clock CpGs [75], and that the epigenetic aging rates are significantly associated with ethnicity [76]. Here we discuss whether CpG sites related to the drug response or ADME would be affected by both the ethnic difference and the epigenetic age difference.…”

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

“…Advances in single cell 'omics' provide a more complex picture of identity, often revealing continuums of multiple facets of cellular plasticity [47]. Therefore, the distinction between DNA methylation changes at single loci within a canonical cell type (intrinsic in Horvath's definition [19]) and changed cell fate characterized by DNA methylation changes at multiple loci (extrinsic by Horvath's definition) is just one of scale. How do we define where variation within a specific cell subtype ends and a new cellular fate begins?…”

“…For instance, if all B cells are methylated at a particular locus, while all other cellular constituents of blood are not, variations in the methylation signal at this locus will reflect (at least in part) the proportion of B cells in a blood sample ( Figure 1B). Horvath et al [19] recently referred to DNA methylation change due to change in cellular proportions as the 'extrinsic' signal. Horvath et al also defined an intrinsic signal as that occurring only within a canonical cell type ( Figure 1C).…”