title: Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder.
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.
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, NewYork, NewYork. Electronic address: rachel.yehuda@va.gov.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Janine D
authors.initials: JD
authors.lastname: Flory
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bierer
authors.affiliation: Department of Neuroscience (RY), Icahn School of Medicine at Mount Sinai, NewYork, NewYork; Steven and Alexandra Cohen Veterans Center for the Study of Posttraumatic Stress and Traumatic Brain Injury (CH-H, CRM), New York University School of Medicine, New York, New York.
authors.forename: Clare
authors.initials: C
authors.lastname: Henn-Haase
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehrner
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Frank
authors.initials: F
authors.lastname: Desarnaud
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Iouri
authors.initials: I
authors.lastname: Makotkine
authors.affiliation: Mental Health Care Center (RY, JDF, LMB, AL, FD, IM, NPD), James J. Peters Veterans Affairs Medical Center, Bronx, New York; Traumatic Stress Studies Division (RY, JDF, LMB, AL, FD, IM, NPD), Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nikolaos P
authors.initials: NP
authors.lastname: Daskalakis
authors.affiliation: Department of Neuroscience (RY), Icahn School of Medicine at Mount Sinai, NewYork, NewYork; Steven and Alexandra Cohen Veterans Center for the Study of Posttraumatic Stress and Traumatic Brain Injury (CH-H, CRM), New York University School of Medicine, New York, New York.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Marmar
authors.affiliation: Department of Psychiatry (CH-H, CRM), New York University School of Medicine, New York, New York; Sackler Program for Epigenetics Psychobiology (MJM), McGill University, Montreal, Canada; Departments of Psychiatry and Neurology &Neurosurgery (MJM), McGill University, Montreal, Canada; and Singapore Institute for Clinical Sciences (MJM), Singapore, Singapore.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meaney
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D003596:Cytosine / Q000737:chemistry; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000150:complications / Q000235:genetics; D003907:Dexamethasone / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D009113:Muramidase / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D014728:Veterans / Q000523:psychology*
chemical_list: D015415:Biomarkers; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D003596:Cytosine; D009113:Muramidase; D006854:Hydrocortisone
keywords: Biomarkers; Combat; Cortisol; Glucocorticoid receptor; HPA axis; Methylation; NR3C1 gene; NR3C1-1(F) promoter; PTSD