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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.Nat Neurosci. 2013; 16: 33-41
- Epigenetic programming by maternal behavior.Nat Neurosci. 2004; 7: 847-854
- Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.Nat Neurosci. 2009; 12: 342-348
- Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis.Endocrinology. 2011; 152: 4496-4503
- Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment.Am J Psychiatry. 2011; 168: 89-96
- The development of a Clinician-Administered PTSD Scale.J Trauma Stress. 1995; 8: 75-90
- Structured Clinical Interview for DSM-IV (SCID).New York State Psychiatric Institute Biometrics Research, New York1995
- The PTSD Checklist Military Version (PCL-M).National Center for PTSD, Boston1991
- Dimensions of dysfunctional attitudes as vulnerabilities to depressive symptoms.J Abnorm Psychol. 1995; 104: 431-435
- Development and preliminary psychometric properties of an instrument for the measurement of childhood trauma: The Early Trauma Inventory.Depress Anxiety. 2000; 12: 1-12
- The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research.Psychiatry Res. 1989; 28: 193-213
- The Peritraumatic Dissociative Experiences Questionnaire.in: Wilson J.P. Keane T.M. Assessing Psychological Trauma and PTSD: A Handbook for Practitioners. Guilford Press, New York1997
Derogatis LR (1992): SCL-90-R: Administration, scoring and procedures manual for the revised version and other instruments of the psychopathology rating scale series. Baltimore: Clinical Psychometric Research, Inc.
- Factors underlying variable DNA methylation in a human community cohort.Proc Natl Acad Sci U S A. 2012; 109: 17253-17260
- Enduring effects of severe developmental adversity, including nutritional deprivation, on cortisol metabolism in aging Holocaust survivors.J Psychiatr Res. 2009; 43: 877-883
- Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD.Front Psychiatry. 2013; 4: 118
- Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone.J Psychiatr Res. 2003; 37: 471-477
- Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment.Psychoneuroendocrinology. 2006; 31: 1181-1189
- Post-traumatic stress disorder.N Engl J Med. 2002; 346: 108-114
- Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed.Psychoneuroendocrinology. 2010; 35: 544-556
- Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.Epigenetics. 2008; 3: 97-106
- Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: Identification, and tissue distribution of multiple new human exon 1.J Mol Endocrinol. 2005; 35: 283-292
- DNA methylation patterns and epigenetic memory.Genes Dev. 2002; 16: 6-21
- Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse.Biol Psychiatry. 2012; 72: 41-48
- Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood.J Psychiatr Res. 2013; 47: 880-891
- Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor.Transl Psychiatry. 2011; 1: e21
- Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma.Transl Psychiatry. 2011; 1: e59
- The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: Altering epigenetic marks by immediate-early genes.J Neurosci. 2007; 27: 1756-1768
- Genomic DNA methylation: The mark and its mediators.Trends Biochem Sci. 2006; 31: 89-97
- Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.Nat Genet. 2007; 39: 457-466
- Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder.Arch Gen Psychiatry. 1995; 52: 583-593
- Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors.Mol Psychiatry. 2005; 10: 500-513
- Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks.Dis Markers. 2011; 30: 101-110
- Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.Biol Psychiatry. 2009; 66: 708-711
- The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders.Psychoneuroendocrinology. 2009; 34: S186-S195
- Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment.Biol Psychiatry. 2001; 49: 391-404
- The corticosteroid receptor hypothesis of depression.Neuropsychopharmacology. 2000; 23: 477-501
- A controlled pore glass bead assay for the measurement of cytoplasmic and nuclear glucocorticoid receptors.J Steroid Biochem. 1985; 22: 693-698
- Glucocorticoid resistance in depression: The dexamethasone suppression test and lymphocyte sensitivity to dexamethasone.Am J Psychiatry. 1984; 141: 1365-1370
- Normal lymphocyte responsiveness to lectins but impaired sensitivity to in vitro glucocorticoids in major depression.J Affect Disord. 1991; 22: 241-248
- Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: A systematic review and meta-analysis.Clin Psychol Rev. 2012; 32: 301-315
- Methylation of the glucocorticoid receptor gene promoter in bulimic women: Associations with borderline personality disorder, suicidality, and exposure to childhood abuse.Int J Eat Disord. 2013; 46: 246-255
- Epigenetic and genetic factors predict women’s salivary cortisol following a threat to the social self.PLoS One. 2012; 7: e48597
- Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults.PLoS One. 2012; 7: e30148
Article Info
Publication History
Published online: February 19, 2014
Accepted:
February 6,
2014
Received in revised form:
January 17,
2014
Received:
November 26,
2013
Identification
Copyright
Published by Elsevier Inc.
