Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder

Biol Psychiatry. 2015 Feb 15;77(4):356-64. doi: 10.1016/j.biopsych.2014.02.006. Epub 2014 Feb 17.


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.

Keywords: Biomarkers; Combat; Cortisol; Glucocorticoid receptor; HPA axis; Methylation; NR3C1 gene; NR3C1-1(F) promoter; PTSD.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Cytosine / chemistry
  • DNA Methylation
  • Depressive Disorder, Major / complications
  • Depressive Disorder, Major / genetics
  • Dexamethasone / metabolism
  • Epigenesis, Genetic
  • Humans
  • Hydrocortisone / urine
  • Hypothalamus / metabolism
  • Male
  • Monocytes / metabolism*
  • Muramidase / metabolism
  • Pituitary-Adrenal System / metabolism
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism*
  • Stress Disorders, Post-Traumatic / complications
  • Stress Disorders, Post-Traumatic / genetics*
  • Stress Disorders, Post-Traumatic / metabolism*
  • Veterans / psychology*


  • Biomarkers
  • NR3C1 protein, human
  • Receptors, Glucocorticoid
  • Dexamethasone
  • Cytosine
  • Muramidase
  • Hydrocortisone