Altered gene expression of the innate immune, neuroendocrine, and nuclear factor-kappa B (NF-κB) systems is associated with posttraumatic stress disorder in military personnel

doi:10.1016/j.janxdis.2015.12.004

Journal of Anxiety Disorders

Volume 38, March 2016, Pages 9-20

https://doi.org/10.1016/j.janxdis.2015.12.004 Get rights and content

Highlights

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A total of 203 genes were differentially expressed in military personnel with PTSD.
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Findings were independent of depression severity, history of TBI, and meditation use.
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IPA identified dysregulated innate immune, glucocorticoid receptor, and NF-κB pathways.
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The PTSD group showed upregulation in pro-inflammatory cytokine genes.
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Findings suggest that inflammation may be a significant factor in PTSD pathogenesis.

Abstract

Whole transcriptome analysis provides an unbiased examination of biological activity, and likely, unique insight into the mechanisms underlying posttraumatic stress disorder (PTSD) and comorbid depression and traumatic brain injury. This study compared gene-expression profiles in military personnel with PTSD (n = 28) and matched controls without PTSD (n = 27) using HG-U133 Plus 2.0 microarrays (Affymetrix), which contain 54,675 probe sets representing more than 38,500 genes. Analysis of expression profiles revealed 203 differentially expressed genes in PTSD, of which 72% were upregulated. Using Partek Genomics Suite 6.6, differentially expressed transcription clusters were filtered based on a selection criterion of ≥1.5 relative fold change at a false discovery rate of ≤5%. Ingenuity Pathway Analysis (Qiagen) of the differentially expressed genes indicated a dysregulation of genes associated with the innate immune, neuroendocrine, and NF-κB systems. These findings provide novel insights that may lead to new pharmaceutical agents for PTSD treatments and help mitigate mental and physical comorbidity risk.

Introduction

Operations Enduring Freedom and Iraqi Freedom have had more than a 90% increase in rates of survival among combat-injured service members, resulting in a cohort of military personnel and veterans with chronic deployment-related disorders (Buckenmaier, Brandon-Edwards, Borden, & Wright, 2010). The combination of physical injury and life-threatening psychological stress can form a complex pathology called posttraumatic stress disorder (PTSD) that manifests as a collection of overlapping behavioral symptoms. Approximately 24% of U.S. military personnel who were deployed to Iraq or Afghanistan developed PTSD, which is highly comorbid with depression and traumatic brain injury (TBI) (Xing et al., 2013, Yurgil et al., 2014). These injuries and related symptoms result in health care costs estimated to be between 4 and 6 trillion dollars annually (Edwards, 2010). Despite this, we remain limited in our ability to treat PTSD due to a lack of clarity regarding the biological mechanisms underlying posttraumatic symptoms. As a result, there is an immediate need to elucidate the biological pathways responsible for PTSD symptoms, while also considering the impact of comorbid depression and TBI-related symptoms, which are common in military personnel (Gill et al., 2014).

PTSD is an anxiety disorder defined as the development of symptoms following exposure to an extreme traumatic event. These symptoms are characterized into three separate but interrelated symptom clusters: intrusion symptoms (nightmares, flashbacks), avoidance and numbing symptoms (avoiding trauma reminders, cognitive difficulties, feeling cut off from loved ones), and hyperarousal symptoms (feeling jumpy, irriTable, sleeping difficulties) (Van Voorhees et al., 2014). In military personnel there is a high prevalence of overlapping symptoms between TBI and other comorbid conditions, including PTSD and depression (Yurgil et al., 2014). TBI results from biomechanical traumas that are frequently sustained in the midst of psychologically traumatic experiences. Similarities in the neuroanatomies of PTSD and TBI further suggest that the overlap in symptoms associated with both conditions may be the result of shared underlying mechanisms (Bahraini et al., 2014). Symptom overlap and lack of objective and specific diagnostic aids or markers to facilitate rapid differential diagnosis makes it difficult to separate the effects of TBI from those of PTSD, which is of great utility for recently deployed military personnel where TBI has become increasingly more common.

PTSD is linked to a dysfunction of the stress-response system, including the hypothalamic–pituitary axis, autonomic and central nervous systems, and neurotransmitter alterations (Mehta and Binder, 2012, van Liempt et al., 2013, Zoladz and Diamond, 2013). The hypothalamic–pituitary axis and sympathetic nervous systems orchestrate the response to stressors, including deployment, and modify the functioning of the immune system (Mehta and Binder, 2012, van Liempt et al., 2013, Zoladz and Diamond, 2013). Sustained stressors, such as deployment, result in high concentrations of inflammatory cytokines (McGowan, 2013; Deppermann, Storchak, Fallgatter, & Ehlis, 2014). We previously report that military personnel with insomnia and a high degree of PTSD and depression symptoms have increased concentrations of inflammatory proteins such as C-reactive protein, with the highest concentrations in individuals with the greatest number of comorbidities (Heinzelmann et al., 2015). Furthermore, we also reported that reductions in sleep disturbance symptoms, following standard of care treatment for insomnia, relate to reductions in inflammation, including reductions in interleukin-6 (Gill et al., 2014). Although inflammation is consistently linked to PTSD, a comprehensive examination of the biological system, as opposed to a focus on a single or a few biomarkers, is optimal to obtain novel insights into the underlying mechanisms. Thus, we propose the use of a transcriptome-wide approach to determine gene profiles related to a complex disorder such as PTSD (Cohen, Kozlovsky, Matar, Zohar, & Kaplan, 2014). This line of research is important, as gene expression studies allow for the evaluation of the ensuing impact of genetic and epigenetic variants, which may ultimately result in the identification of biomarkers that underlie PTSD symptomology.

Previous gene expression studies suggest that central processes related to PTSD can be detected in peripheral samples of blood (Tylee, Kawaguchi, & Glatt, 2013). Specifically, in a study of individuals who developed PTSD following the September 11th attacks gene expression profiles were altered, which included signal transduction and activation of transcription 5B (STAT5B), a gene that directly inhibits glucocorticoid receptor activity (Sarapas et al., 2011). In a novel study of Marines who were examined prior to deployment, reduced expression of oxidative stress genes including glutathione s-transferase mu 1 (GSTM1) and glutathione s-transferase mu 2 (GSTM2) increased the risk of developing PTSD. Other studies of gene expression in military personnel with PTSD report alterations in the activity of genes in the nuclear factor-kappa B (NF-κB) pathway, which regulates inflammatory gene networks (Glatt et al., 2013, Tylee et al., 2014). This group has further replicated and expanded on these findings through unique systems-level integration methods (Breen et al., 2015). Recently, a large study of military personnel found that PTSD was associated with reduced expression of glucocorticoid signaling genes, as well as down syndrome cell adhesion molecule (DSCAM), which are necessary to regulate inflammation and promote neurological development and maintenance, respectively. These results remained significant after controlling for depression, medication use, and substance use, but the analysis did not consider the possible impact of TBI (Logue et al., 2015). Therefore, current studies link PTSD to altered gene expression, yet the impact of comorbid depression and TBI, which are associated with unique gene expression profiles (Heinzelmann et al., 2014a, Heinzelmann et al., 2014b, Uher, 2014), as well as distant inflammatory profiles in proteins (Gill et al., 2014), has not yet been determined. This leads us to question if a whole-genome examination of PTSD, which further controls for the impact of comorbid depression and TBI, will provide additional insight in understanding the mechanisms of PTSD, as well as related comorbidity risks.

Section snippets

Participants

This study was an observational assessment of 55 active duty U.S. military personnel recruited from the greater D.C. area. Exclusion criteria included (1) a history of drug or alcohol abuse in the previous year, (2) a current medical condition that required substantial treatment (i.e., stroke, diabetes, or autoimmune disorders), and (3) a severe psychiatric condition (i.e., schizophrenia or bipolar disorder). PTSD participants (n = 28) were determined to have a high degree of PTSD symptoms

Gene expression analysis

Clinical variables were compared using analyses of variance models (ANOVA) for continuous variables and chi-square for categorical data. Bonferroni corrections were used to adjust for multiple comparisons using SPSS version 21 (IBM Corp., Armonk, NY). Partek Genomics Suite software, version 6.6 (Partek Inc., St. Louis, MO), was utilized for all analytic procedures performed on microarray data. Interrogating probes were imported, and corrections for background signal were applied using the

Demographics & clinical characteristics

Table 1 presents the demographic and clinical characteristics of the 55 participants included in this analysis. Approximately 42% of the participants reported current use of relevant medications including antidepressants (39%), narcotics (23%), benzodiazepines (7%), non-benzodiazepine receptor agonists (7%), and prazosin (7%). The PTSD and control groups did not differ in the number and type of medication they were taking. The 28 PTSD participants had a mean score of 60.1 (SD 5.6) on the PCL-M,

Discussion

The underlying neurobiological mechanisms of PTSD and comorbid conditions remain only partially understood, which contribute to a significant challenge in treating the rapidly growing population of active-duty military and veterans exhibiting PTSD symptomology and related comorbidities. Using a whole genome expression analysis of peripheral blood, this study reports a total of 203 differentially expressed genes in the PTSD group, which remained significant after accounting for depression

Conclusion

Our findings suggest that PTSD in military personnel is associated with differential gene expression profiles compared to matched controls, even after controlling for symptoms of depression, history of TBI, and relevant medication use. Specifically, we report that PTSD is associated with altered gene expression associated with the innate immune, neuroendocrine, and NF-κB systems, which have implications for increased risk for mental and physical comorbidity that have been consistently linked to

Conflict of interest

The authors declare no conflict of interest.

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Altered gene expression of the innate immune, neuroendocrine, and nuclear factor-kappa B (NF-κB) systems is associated with posttraumatic stress disorder in military personnel

Highlights

Abstract

Introduction

Section snippets

Participants

Gene expression analysis

Demographics & clinical characteristics

Discussion

Conclusion

Conflict of interest

Neuropharmacology

Advances in Integrative Medicine

Psychiatric Clinics of North America

European Neuropsychopharmacology

Neuroscience

Progress in Neuropsychopharmacology & Biological Psychiatry

Biological Psychiatry

Psychiatry Research

Biological Psychiatry

Journal of Psychosomatic Research

Pharmacology Biochemistry and Behavior

Brain, Behavior, and Immunity

Psychoneuroendocrinology

Neuropharmacology

Biological Psychiatry

Biological Psychiatry

Psychoneuroendocrinology

Neurotoxicology and Teratology

Brain, Behavior, and Immunity

Biological Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

Psychoneuroendocrinology

Brain, Behavior, and Immunity

Behavioural Brain Research

Neuroscience & Biobehavioral Reviews

Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases

Endocrine Reviews

Gene networks specific for innate immunity define post-traumatic stress disorder

Molecular Psychiatry

Treating pain on the battlefield: a warrior’s perspective

Current Pain and Headache Reports

The characteristic long-term upregulation of hippocampal NF-kappaB complex in PTSD-like behavioral stress response is normalized by high-dose corticosterone and pyrrolidine dithiocarbamate administered immediately after exposure

Neuropsychopharmacology

Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder

Molecular Psychiatry