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EBioMedicine. 2017 Apr;18:327-350. doi: 10.1016/j.ebiom.2017.03.044. Epub 2017 Apr 4.

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

Author information

1
Harvard/MGH Center on Genomics, Vulnerable Populations, and Health Disparities, Department of Medicine, Massachusetts General Hospital, 50 Staniford St., Suite 901, Boston, MA 02114, USA.
2
Department of Pediatrics, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11218, USA.
3
Harvard/MGH Center on Genomics, Vulnerable Populations, and Health Disparities, Department of Medicine, Massachusetts General Hospital, 50 Staniford St., Suite 901, Boston, MA 02114, USA; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, 722 W. 168th St., 11th Floor, New York, NY 10032, USA.
4
Harvard/MGH Center on Genomics, Vulnerable Populations, and Health Disparities, Department of Medicine, Massachusetts General Hospital, 50 Staniford St., Suite 901, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA. Electronic address: ashields@partners.org.

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.

KEYWORDS:

Adverse childhood experiences (ACE); Alzheimer's; Cancer; Depression; FKBP5; Glucocorticoids; HPA axis; HSD11β2; Hypertension; Methylation; NR3C1; PTSD; Stress

PMID:
28434943
PMCID:
PMC5405197
DOI:
10.1016/j.ebiom.2017.03.044
[Indexed for MEDLINE]
Free PMC Article

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