Elsevier

Biological Psychiatry

Volume 77, Issue 4, 15 February 2015, Pages 356-364
Biological Psychiatry

Archival Report
Lower Methylation of Glucocorticoid Receptor Gene Promoter 1F in Peripheral Blood of Veterans with Posttraumatic Stress Disorder

https://doi.org/10.1016/j.biopsych.2014.02.006Get rights and content

Abstract

Background

Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors.

Methods

Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans.

Results

Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs’ lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD.

Conclusions

Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

Section snippets

Participants and Clinical Assessment

This article reports on data from 122 participants (61 with PTSD, 61 without PTSD) in whom NR3C1-1F promoter methylation and gene expression was determined in PBMCs, in addition to other neuroendocrine biomarkers. Participants were recruited as part of a larger study that was designed as an initial investigation of male combat veterans, to be followed by a replication and longitudinal validation study in men and women. Combat veterans were recruited at two sites, the James J. Peters Veterans

Demographic and Clinical Information

Table 1 presents demographic and clinical characteristics of the PTSD+ and PTSD− groups. Because the sample was intentionally selected to be comparable in age, race, and ethnicity, there were no group differences for these variables. Early trauma exposure scores (on the Early Trauma Inventory) ranged from 0−21, and the groups did not differ. The PTSD+ group reported higher scores on measures of PTSD-related symptoms (Table 1). There were no differences in the lymphocyte or monocyte numbers or

Discussion

This is the first report of NR3C1-1F promoter methylation in purified PBMCs in individuals with PTSD. The primary focus was on DNA methylation, which is a comparatively stable biochemical modification (as opposed to GR transcription, which can vary dynamically in association with prevailing contextual influences). The NR3C1-1F promoter was examined because it is also highly active in brain tissue (22). The NR3C1-1F promoter lies within a CpG island located immediately upstream of the exon NR3C1

Acknowledgments and Disclosures

This work was supported by grant funding from the Department of Defense (Grant No. W911NF-09-1-0298 to RY and Grant No. W81XWH-09-2-0044 to CRM). We thank Dr. Owen Wolkowitz for scientific collaboration and for funding that permitted additional recruitment (Department of Defense Grant No. W81XWH-10-1-0021).

The authors report no biomedical financial interests or potential conflicts of interest.

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