Epigenome-wide mediation analysis of the relationship between psychosocial stress and cardiometabolic risk factors in the Health and Retirement Study (HRS)

Background: Exposure to psychosocial stress is linked to a variety of negative health outcomes, including cardiovascular disease and its cardiometabolic risk factors. DNA methylation has been associated with both psychosocial stress and cardiometabolic disease; however, little is known about the mediating role of DNA methylation on the association between stress and cardiometabolic risk. Thus, using the high-dimensional mediation testing method, we conducted an epigenome-wide mediation analysis of the relationship between psychosocial stress and ten cardiometabolic risk factors in a multi-racial/ethnic population of older adults (n = 2668) from the Health and Retirement Study (mean age = 70.4 years). Results: A total of 50, 46, 7, and 12 CpG sites across the epigenome mediated the total effects of stress on body mass index, waist circumference, high-density lipoprotein cholesterol, and C-reactive protein, respectively. When reducing the dimensionality of the CpG mediators to their top 10 uncorrelated principal components (PC), the cumulative effect of the PCs explained between 35.8 and 46.3% of these associations. Conclusions: A subset of the mediating CpG sites were associated with the expression of genes enriched in pathways related to cytokine binding and receptor activity, as well as neuron development. Findings from this study help to elucidate the underlying mechanisms through which DNA methylation partially mediates the relationship between psychosocial stress and cardiometabolic risk factors.