Effects of early- and mid-life stress on DNA methylation of genes associated with subclinical cardiovascular disease and cognitive impairment: a systematic review

BackgroundTraditional and novel risk factors cannot sufficiently explain the differential susceptibility to cardiovascular disease (CVD). Epigenetics may serve to partially explain this residual disparity, with life course stressors shown to modify methylation of genes implicated in various diseases. Subclinical CVD is often comorbid with cognitive impairment (CI), which warrants research into the identification of common genes for both conditions.MethodsWe conducted a systematic review of the existing literature to identify studies depicting the relationship between life course stressors, DNA methylation, subclinical CVD, and cognition.ResultsA total of 16 articles (8 human and 8 animal) were identified, with the earliest published in 2008. Four genes (COMT, NOS3, Igfl1, and Sod2) were analyzed by more than one study, but not in association with both CVD and CI. One gene (NR3C1) was associated with both outcomes, albeit not within the same study. There was some consistency among studies with markers used for subclinical CVD and cognition, but considerable variability in stress exposure (especially in human studies), cell type/tissue of interest, method for detection of DNA methylation, and risk factors. Racial and ethnic differences were not considered, but analysis of sex in one human study found statistically significant differentially methylated X-linked loci associated with attention and intelligence.ConclusionsThis review suggests the need for additional studies to implement more comprehensive and methodologically rigorous study designs that can better identify epigenetic biomarkers to differentiate individuals vulnerable to both subclinical CVD and associated CI.