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

  • Rachel Yehuda
    Correspondence
    Address correspondence to Rachel Yehuda, Ph.D., Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, James J. Peters Veterans Affairs Medical Center, 526 OOMH PTSD 116/A, 130 West Kingsbridge Road, Bronx, New York 10468
    Affiliations
    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
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  • Janine D. Flory
    Affiliations
    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
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  • Linda M. Bierer
    Affiliations
    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
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  • Clare Henn-Haase
    Affiliations
    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
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  • Amy Lehrner
    Affiliations
    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
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  • Frank Desarnaud
    Affiliations
    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
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  • Iouri Makotkine
    Affiliations
    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
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  • Nikolaos P. Daskalakis
    Affiliations
    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
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  • Charles R. Marmar
    Affiliations
    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
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  • Michael J. Meaney
    Affiliations
    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
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Published:February 19, 2014DOI:https://doi.org/10.1016/j.biopsych.2014.02.006

      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.

      Keywords

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