Advertisement

Glucocorticoid Receptor Pathway Components Predict Posttraumatic Stress Disorder Symptom Development: A Prospective Study

  • Mirjam van Zuiden
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands

    Research Centre-Military Mental Health, Ministry of Defence, Utrecht, The Netherlands
    Search for articles by this author
  • Elbert Geuze
    Affiliations
    Research Centre-Military Mental Health, Ministry of Defence, Utrecht, The Netherlands

    Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Hanneke L.D.M. Willemen
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Eric Vermetten
    Affiliations
    Research Centre-Military Mental Health, Ministry of Defence, Utrecht, The Netherlands

    Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Mirjam Maas
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Karima Amarouchi
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Annemieke Kavelaars
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
  • Cobi J. Heijnen
    Correspondence
    Address correspondence to Cobi J. Heijnen, Ph.D., Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Room KC03.068.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
    Affiliations
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
    Search for articles by this author
Published:December 05, 2011DOI:https://doi.org/10.1016/j.biopsych.2011.10.026

      Background

      Biological correlates of posttraumatic stress disorder (PTSD) have mostly been studied using cross-sectional or posttrauma prospective designs. Therefore, it remains largely unknown whether previously observed biological correlates of PTSD precede trauma exposure. We investigated whether glucocorticoid receptor (GR) pathway components assessed in leukocytes before military deployment represent preexisting vulnerability factors for development of PTSD symptoms.

      Methods

      Four hundred forty-eight male soldiers were assessed before and 6 months after deployment to a combat zone. Participants were assigned to the PTSD or comparison group based on Self-Rating Inventory for PTSD scores after deployment. Logistic regression analysis was applied to predict development of a high level of PTSD symptoms based on predeployment GR number, messenger (m)RNA expression of GR target genes FKBP5, GILZ, and SGK1, plasma cortisol, and childhood trauma. We also investigated whether predeployment GR number and FKBP5 mRNA expression were associated with single nucleotide polymorphisms in the GR and FKBP5 genes, either alone or in interaction with childhood trauma.

      Results

      Several GR pathway components predicted subsequent development of a high level of PTSD symptoms: predeployment high GR number, low FKBP5 mRNA expression, and high GILZ mRNA expression were independently associated with increased risk for a high level of PTSD symptoms. Childhood trauma also independently predicted development of a high level of PTSD symptoms. Additionally, we observed a significant interaction effect of GR haplotype BclI and childhood trauma on GR number.

      Conclusions

      Collectively, our results indicate that predeployment GR pathway components are vulnerability factors for subsequent development of a high level of PTSD symptoms.

      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 access
      One-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 Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • de Vries G.J.
        • Olff M.
        The lifetime prevalence of traumatic events and posttraumatic stress disorder in the Netherlands.
        J Trauma Stress. 2009; 22: 259-267
        • Heim C.
        • Nemeroff C.B.
        Neurobiology of posttraumatic stress disorder.
        CNS Spectr. 2009; 14: 13-24
        • Meewisse M.L.
        • Reitsma J.B.
        • de Vries G.J.
        • Gersons B.P.
        • Olff M.
        Cortisol and post-traumatic stress disorder in adults: Systematic review and meta-analysis.
        Br J Psychiatry. 2007; 191: 387-392
        • Inslicht S.S.
        • Marmar C.R.
        • Neylan T.C.
        • Metzler T.J.
        • Hart S.L.
        • Otte C.
        • et al.
        Increased cortisol in women with intimate partner violence-related posttraumatic stress disorder.
        Psychoneuroendocrinology. 2006; 31: 825-838
        • Otte C.
        • Lenoci M.
        • Metzler T.
        • Yehuda R.
        • Marmar C.R.
        • Neylan T.C.
        Hypothalamic-pituitary-adrenal axis activity and sleep in posttraumatic stress disorder.
        Neuropsychopharmacology. 2005; 30: 1173-1180
        • Steudte S.
        • Kolassa I.T.
        • Stalder T.
        • Pfeiffer A.
        • Kirschbaum C.
        • Elbert T.
        Increased cortisol concentrations in hair of severely traumatized Ugandan individuals with PTSD.
        Psychoneuroendocrinology. 2011; 36: 1193-1200
        • Lindley S.E.
        • Carlson E.B.
        • Benoit M.
        Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder.
        Biol Psychiatry. 2004; 55: 940-945
        • Rohleder N.
        • Wolf J.M.
        • Wolf O.T.
        Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder.
        Neurosci Biobehav Rev. 2010; 35: 104-114
        • de Kloet C.S.
        • Vermetten E.
        • Heijnen C.J.
        • Geuze E.
        • Lentjes E.G.
        • Westenberg H.G.
        Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder.
        Psychoneuroendocrinology. 2007; 32: 215-226
        • Golier J.A.
        • Schmeidler J.
        • Legge J.
        • Yehuda R.
        Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment.
        Psychoneuroendocrinology. 2006; 31: 1181-1189
        • Klaassens E.R.
        • Giltay E.J.
        • Cuijpers P.
        • van Veen T.
        • Zitman F.G.
        Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: A meta-analysis [published online ahead of print July 28].
        Psychoneuroendocrinology. 2011;
        • Yehuda R.
        • Yang R.K.
        • Golier J.A.
        • Grossman R.A.
        • Bierer L.M.
        • Tischler L.
        Effect of sertraline on glucocorticoid sensitivity of mononuclear leukocytes in post-traumatic stress disorder.
        Neuropsychopharmacology. 2006; 31: 189-196
        • Rohleder N.
        • Joksimovic L.
        • Wolf J.M.
        • Kirschbaum C.
        Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.
        Biol Psychiatry. 2004; 55: 745-751
        • de Kloet C.S.
        • Vermetten E.
        • Bikker A.
        • Meulman E.
        • Geuze E.
        • Kavelaars A.
        • et al.
        Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder.
        Mol Psychiatry. 2007; 12: 443-453
        • De Bosscher K.
        • Beck I.M.
        • Haegeman G.
        Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: Survival of the fittest regulator of the immune system?.
        Brain Behav Immun. 2010; 24: 1035-1042
        • Armanini D.
        • Spinella P.
        • Simoncini M.
        • Basso A.
        • Zovato S.
        • Pozzan G.B.
        • et al.
        Regulation of corticosteroid receptors in patients with anorexia nervosa and Cushing's syndrome.
        J Endocrinol. 1998; 158: 435-439
        • Hagendorf A.
        • Koper J.W.
        • de Jong F.H.
        • Brinkmann A.O.
        • Lamberts S.W.
        • Feelders R.A.
        Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism.
        J Clin Endocrinol Metab. 2005; 90: 6237-6243
        • Kino T.
        • Su Y.A.
        • Chrousos G.P.
        Human glucocorticoid receptor isoform beta: Recent understanding of its potential implications in physiology and pathophysiology.
        Cell Mol Life Sci. 2009; 66: 3435-3448
        • Yehuda R.
        • Lowy M.T.
        • Southwick S.M.
        • Shaffer D.
        • Giller Jr, E.L.
        Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder.
        Am J Psychiatry. 1991; 148: 499-504
        • Yehuda R.
        • Boisoneau D.
        • Mason J.W.
        • Giller E.L.
        Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders.
        Biol Psychiatry. 1993; 34: 18-25
        • Denny W.B.
        • Valentine D.L.
        • Reynolds P.D.
        • Smith D.F.
        • Scammell J.G.
        Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding.
        Endocrinology. 2000; 141: 4107-4113
        • Yehuda R.
        • Cai G.
        • Golier J.A.
        • Sarapas C.
        • Galea S.
        • Ising M.
        • et al.
        Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.
        Biol Psychiatry. 2009; 66: 708-711
        • Sarapas C.
        • Cai G.
        • Bierer L.M.
        • Golier J.A.
        • Galea S.
        • Ising M.
        • et al.
        Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks.
        Dis Markers. 2011; 30: 101-110
        • Segman R.H.
        • Shefi N.
        • Goltser-Dubner T.
        • Friedman N.
        • Kaminski N.
        • Shalev A.Y.
        Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors.
        Mol Psychiatry. 2005; 10 (425): 500-513
        • van Zuiden M.
        • Geuze E.
        • Willemen H.L.
        • Vermetten E.
        • Maas M.
        • Heijnen C.J.
        • et al.
        Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment.
        Am J Psychiatry. 2011; 168: 89-96
        • De Bosscher K.
        • Vanden Berghe W.
        • Haegeman G.
        The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: Molecular mechanisms for gene repression.
        Endocr Rev. 2003; 24: 488-522
        • Ayroldi E.
        • Riccardi C.
        Glucocorticoid-induced leucine zipper (GILZ): A new important mediator of glucocorticoid action.
        FASEB J. 2009; 23: 3649-3658
        • Luca F.
        • Kashyap S.
        • Southard C.
        • Zou M.
        • Witonsky D.
        • Di Rienzo A.
        • et al.
        Adaptive variation regulates the expression of the human SGK1 gene in response to stress.
        PLoS Genet. 2009; 5: e1000489
        • Brewin C.R.
        • Andrews B.
        • Valentine J.D.
        Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults.
        J Consult Clin Psychol. 2000; 68: 748-766
        • Derijk R.H.
        Single nucleotide polymorphisms related to HPA axis reactivity.
        Neuroimmunomodulation. 2009; 16: 340-352
        • Kumsta R.
        • Entringer S.
        • Koper J.W.
        • van Rossum E.F.
        • Hellhammer D.H.
        • Wust S.
        Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.
        Biol Psychiatry. 2007; 62: 863-869
        • Hauer D.
        • Weis F.
        • Papassotiropoulos A.
        • Schmoeckel M.
        • Beiras-Fernandez A.
        • Lieke J.
        • et al.
        Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy.
        Crit Care Med. 2011; 39: 643-650
        • Koenen K.C.
        • Saxe G.
        • Purcell S.
        • Smoller J.W.
        • Bartholomew D.
        • Miller A.
        • et al.
        Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children.
        Mol Psychiatry. 2005; 10: 1058-1059
        • Binder E.B.
        • Bradley R.G.
        • Liu W.
        • Epstein M.P.
        • Deveau T.C.
        • Mercer K.B.
        • et al.
        Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults.
        JAMA. 2008; 299: 1291-1305
        • Xie P.
        • Kranzler H.R.
        • Poling J.
        • Stein M.B.
        • Anton R.F.
        • Farrer L.A.
        • et al.
        Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.
        Neuropsychopharmacology. 2010; 35: 1684-1692
        • Hovens J.E.
        • van der Ploeg H.M.
        • Bramsen I.
        • Klaarenbeek M.T.A.
        • Schreuder J.N.
        • Rivero V.V.
        The development of the self-rating inventory for posttraumatic stress disorder.
        Acta Psychiatr Scand. 1994; 90: 172-183
        • Hovens J.E.
        • Bramsen I.
        • van der Ploeg H.M.
        Self-rating inventory for posttraumatic stress disorder: Review of the psychometric properties of a new brief Dutch screening instrument.
        Percept Mot Skills. 2002; 94: 996-1008
        • van Zelst W.H.
        • de Beurs E.
        • Beekman A.T.
        • Deeg D.J.
        • Bramsen I.
        • van Dyck R.
        Criterion validity of the self-rating inventory for posttraumatic stress disorder (SRIP) in the community of older adults.
        J Affect Disord. 2003; 76: 229-235
        • Arrindell W.A.
        • Ettema J.H.M.
        Symptom Checklist: handleiding bij een multidimensionele psychopathologie-indicator.
        ([Symptom Checklist: Manual for a multidimensional indicator of psychopathology]) Swets & Zeitlinger, Lisse, The Netherlands2003
        • Schmitz N.
        • Kruse J.
        • Heckrath C.
        • Alberti L.
        • Tress W.
        Diagnosing mental disorders in primary care: The General Health Questionnaire (GHQ) and the Symptom Check List (SCL-90-R) as screening instruments.
        Soc Psychiatry Psychiatr Epidemiol. 1999; 34: 360-366
        • Aben I.
        • Verhey F.
        • Lousberg R.
        • Lodder J.
        • Honig A.
        Validity of the beck depression inventory, hospital anxiety and depression scale, SCL-90, and Hamilton Depression Rating Scale as screening instruments for depression in stroke patients.
        Psychosomatics. 2002; 43: 386-393
        • Strik J.J.
        • Honig A.
        • Lousberg R.
        • Denollet J.
        Sensitivity and specificity of observer and self-report questionnaires in major and minor depression following myocardial infarction.
        Psychosomatics. 2001; 42: 423-428
        • Bremner J.D.
        • Bolus R.
        • Mayer E.A.
        Psychometric properties of the Early Trauma Inventory-Self Report.
        J Nerv Ment Dis. 2007; 195: 211-218
        • van Zuiden M.
        • Geuze E.
        • Maas M.
        • Vermetten E.
        • Heijnen C.J.
        • Kavelaars A.
        Deployment-related severe fatigue with depressive symptoms is associated with increased glucocorticoid binding to peripheral blood mononuclear cells.
        Brain Behav Immun. 2009; 23: 1132-1139
        • Barrett J.C.
        • Fry B.
        • Maller J.
        • Daly M.J.
        Haploview: Analysis and visualization of LD and haplotype maps.
        Bioinformatics. 2005; 21: 263-265
        • Stephens M.
        • Donnelly P.
        A comparison of bayesian methods for haplotype reconstruction from population genotype data.
        Am J Hum Genet. 2003; 73: 1162-1169
        • Rohleder N.
        • Joksimovic L.
        • Wolf J.M.
        • Kirschbaum C.
        Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.
        Biol Psychiatry. 2004; 55: 745-751
        • Yehuda R.
        • Golier J.A.
        • Yang R.
        • Tischler L.
        Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder.
        Biol Psychiatry. 2004; 55: 1110-1116
        • Inslicht S.S.
        • Otte C.
        • McCaslin S.E.
        • Apfel B.A.
        • Henn-Haase C.
        • Metzler T.
        • et al.
        Cortisol awakening response prospectively predicts peritraumatic and acute stress reactions in police officers.
        Biol Psychiatry. 2011; 70: 1055-1062
        • Ehring T.
        • Ehlers A.
        • Cleare A.J.
        • Glucksman E.
        Do acute psychological and psychobiological responses to trauma predict subsequent symptom severities of PTSD and depression?.
        Psychiatry Res. 2008; 161: 67-75
        • van Zuiden M.
        • Kavelaars A.
        • Rademaker A.R.
        • Vermetten E.
        • Heijnen C.J.
        • Geuze E.
        A prospective study on personality and the cortisol awakening response to predict posttraumatic stress symptoms in response to military deployment.
        J Psychiatr Res. 2011; 45: 713-719
        • Heinrichs M.
        • Wagner D.
        • Schoch W.
        • Soravia L.M.
        • Hellhammer D.H.
        • Ehlert U.
        Predicting posttraumatic stress symptoms from pretraumatic risk factors: A 2-year prospective follow-up study in firefighters.
        Am J Psychiatry. 2005; 162: 2276-2286
        • Lowy M.T.
        Quantification of type I and II adrenal steroid receptors in neuronal, lymphoid and pituitary tissues.
        Brain Res. 1989; 503: 191-197
        • Spencer R.L.
        • Miller A.H.
        • Stein M.
        • McEwen B.S.
        Corticosterone regulation of type I and type II adrenal steroid receptors in brain, pituitary, and immune tissue.
        Brain Res. 1991; 549: 236-246
        • Rohleder N.
        • Wolf J.M.
        • Wolf O.T.
        Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder.
        Neurosci Biobehav Rev. 2010; 35: 104-114
        • Yehuda R.
        • Golier J.A.
        • Bierer L.M.
        • Mikhno A.
        • Pratchett L.C.
        • Burton C.L.
        • et al.
        Hydrocortisone responsiveness in Gulf War veterans with PTSD: Effects on ACTH, declarative memory hippocampal [(18)F]FDG uptake on PET.
        Psychiatry Res. 2010; 184: 117-127
        • Steiniger B.
        • Kniess T.
        • Bergmann R.
        • Pietzsch J.
        • Wuest F.R.
        Radiolabeled glucocorticoids as molecular probes for imaging brain glucocorticoid receptors by means of positron emission tomography (PET).
        Mini Rev Med Chem. 2008; 8: 728-739
        • Mehta D.
        • Gonik M.
        • Klengel T.
        • Rex-Haffner M.
        • Menke A.
        • Rubel J.
        • et al.
        Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies.
        Arch Gen Psychiatry. 2011; 68: 901-910