Pre-Existing High Glucocorticoid Receptor Number Predicting Development of Posttraumatic Stress Symptoms After Military Deployment

Department of Psychiatry , University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
American Journal of Psychiatry (Impact Factor: 12.3). 11/2010; 168(1):89-96. DOI: 10.1176/appi.ajp.2010.10050706
Source: PubMed


The development of posttraumatic stress disorder (PTSD) is influenced by preexisting vulnerability factors. The authors aimed at identifying a preexisting biomarker representing a vulnerability factor for the development of PTSD. To that end, they determined whether the dexamethasone binding capacity of leukocytes, as a measure of glucocorticoid receptor (GR) number, before exposure to trauma was a predictor of development of PTSD symptoms. In addition, the authors analyzed mRNA expression for GR subtypes and GR target genes.
Participants were selected from a large prospective study on deployment-related disorders, in which peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 and 6 months after military deployment. Participants included armed forces personnel with high levels of PTSD symptoms 6 months after deployment (N=34) and comparison subjects without high levels of PTSD or depressive symptoms (N=34) matched for age, rank, previous deployments, educational level, and function during deployment.
Before military deployment, the GR number in PBMCs was significantly higher in participants who developed high levels of PTSD symptoms after deployment relative to matched comparison subjects. Logistic regression analysis showed that the risk for inclusion in the PTSD group after deployment increased 7.5-fold with each GR increase of 1,000. No group differences were observed in mRNA expression of GR-α, GR-P, GR-β, glucocorticoid-induced leucine zipper (GILZ), serum and glucocorticoid-inducible kinase-1 (SGK-1), and FKBP5. The higher GR number in the PTSD group was maintained at 1 and 6 months after deployment.
These results demonstrate that a preexisting high GR number in PBMCs is a vulnerability factor for subsequent development of PTSD symptoms.

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Available from: Elbert Geuze, Sep 09, 2015
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    • "This inhibitory signaling is mediated by glucocorticoid receptor proteins encoded by the gene NRC31 (DeRijk et al., 2008; McEwen, 2012; Meaney, 2001; Sapolsky, Romero, & Munck, 2000). Dysregulated glucocorticoid signaling disrupts HPA axis response to and recovery from a wide range of stressors, and has been implicated in child and adult manifestations of externalizing psychopathology (Fardet, Petersen, & Nazareth, 2012; Hawes, Brennan, & Dadds, 2009; Lopez-Duran et al., 2009; McBurnett et al., 1991; Savitz, Lucki, & Drevets, 2009; Stadler, Poustka, & Sterzer, 2010; van Zuiden et al., 2011). Particularly relevant to the current study is evidence that children exhibiting low cortisol reactivity to experimental challenge respond less favorably than high cortisol-reactive children to an intervention designed to reduce disruptive behavior (van de Wiel et al., 2004). "
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    ABSTRACT: Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.
    Journal of Policy Analysis and Management 06/2015; 34(3). DOI:10.1002/pam.21811 · 0.93 Impact Factor
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    • "The increased sensitivity of the HPA axis, including altered baseline cortisol levels and an increased sensitivity of the GR, can also be induced by adulthood trauma exposure independent of PTSD [22,23]. The increased sensitivity of GRs and the receptor expression may be a consequence of specific genetic backgrounds associated with GR genotypes [24,25]. Although a number of studies have also shown that GR polymorphisms are associated with changes in GCs sensitivity or altered cortisol [24,26,27], few studies have indicated that PTSD is associated with the presence of single nucleotide polymorphisms (SNPs) in genes associated with GR. "
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    ABSTRACT: Background It is debatable whether or not glucocorticoid receptor (GR) polymorphisms moderate susceptibility to PTSD. Our objective was to examine the effects of stressful life events, social support, GR genotypes, and gene-environment interactions on the etiology of PTSD.Methods Three tag single nucleotide polymorphisms, trauma events, stressful life events, and social support were assessed in 460 patients with PTSD and 1158 control subjects from a Chinese Han population. Gene¿environment interactions were analyzed by generalized multifactor dimensionality reduction (GMDR).ResultsVariation in GR at rs41423247 and rs258747, stressful life events, social support, and the number of traumatic events were each separately associated with the risk for PTSD. A gene¿environment interaction among the polymorphisms, rs41423247 and rs258747, the number of traumatic events, stressful life events, and social support resulted in an increased risk for PTSD. High-risk individuals (a large number of traumatic events, G allele of rs258747 and rs41423247, high level stressful life events, and low social support) had a 3.26-fold increased risk of developing PTSD compared to low-risk individuals. The association was statistically significant in the sub-groups with and without childhood trauma.Conclusions Our data support the notion that stressful life events, the number of trauma events, and social support may play a contributing role in the risk for PTSD by interacting with GR gene polymorphisms.
    BMC Psychiatry 08/2014; 14(1):232. DOI:10.1186/s12888-014-0232-9 · 2.21 Impact Factor
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    • "At T1, exposure to combat stressors was assessed with a 13-item Deployment Stressors Checklist that was specifically developed for this study (Van Zuiden et al., 2011a). Items refer to specific events, for example " Exposure to enemy fire (yes/no) " , " Being the target of enemy fire (yes/no) " , and " Being held at gunpoint (yes/no) " . "
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    Psychoneuroendocrinology 07/2014; 51. DOI:10.1016/j.psyneuen.2014.07.010 · 4.94 Impact Factor
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