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

摘要

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.