Epigenetic Pathways in Human Disease: The Impact of DNA Methylation on Stress-Related Pathogenesis and Current Challenges in Biomarker Development

Abstract

HPA axis genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of glucocorticoid regulation in the etiology of disease. We conducted a systematic review to critically assess the full range of clinical associations that have been reported in relation to DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11β1/2 genes in adults. A total of 32 studies were identified. There is prospective evidence for an association between HSD11β2 methylation and hypertension, and functional evidence of an association between NR3C1 methylation and both small cell lung cancer (SCLC) and breast cancer. Strong associations have been reported between FKBP5 and NR3C1 methylation and PTSD, and biologically-plausible associations have been reported between FKBP5 methylation and Alzheimer's Disease. Mixed associations between NR3C1 methylation and mental health outcomes have been reported according to different social and environmental exposures, and according to varying gene regions investigated. We conclude by highlighting key challenges and future research directions that will need to be addressed in order to develop both clinically meaningful prognostic biomarkers and an evidence base that can inform public policy practice.

Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

“…Subsequent studies have built on this information by examining the 1F exon promoter, a relatively small area of the GR gene. In fact, there may be numerous other areas of interest on the GR and other genes that have yet to be identified.…”

New research directions on disparities in obesity and type 2 diabetes

“…Psychosocial stress, which includes diverse stressors at the individual and community levels (e.g., physical and sexual abuse, neighborhood-level poverty, work stress, and discrimination), has been shown to increase individuals' risk of many chronic diseases. 88 Telomere length is another valuable biomarker for exploring the role of psychosocial stress in disease. 83 Stress at work and home, financial stress, depression, and perceived inability to control life circumstances have been associated with increased risk of acute myocardial infarction.…”

“…Altered DNA methylation in hypothalamic-pituitary-adrenal axis (i.e., stress related) genes has been associated with increased risk of hypertension, certain cancers, and posttraumatic stress disorders. 88 Telomere length is another valuable biomarker for exploring the role of psychosocial stress in disease. Telomeres contribute to cell senescence and longevity, and measures of psychosocial stress have been associated with accelerated telomere shortening.…”

Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders

“…18 Methylation of sites associated with the hypothalamuspituitary axis is thought to be involved in the aetiology of a spectrum of age-related diseases including Alzheimer disease, chronic kidney disease, and small cell lung cancer. 19 This association plugs into both the Barker hypothesis 20 and Sapolsky hypothesis linking stress to neuronal death. 21 There may be bidirectional effects, but epigenetic drift is constrained over the human life-course with high heritability, indicating that most DNA methylation is genetically determined.…”