Biomarker Of Posttraumatic Stress Disorder Research Articles

Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development

Post-traumatic stress disorder (PTSD) is a condition of stress reactivity, whose clinical manifestations are evident when patients are triggered following exposure to a traumatic event. While baseline differences in gene expression of glucocorticoid signaling and inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) have been associated with PTSD, these alterations do not fully recapitulate the molecular response to physiological triggers, such as stress hormones. Therefore, it is critical to develop new techniques that will capture the dynamic transcriptional response associated with stress-activated conditions relative to baseline conditions. To achieve this goal, cultured PBMCs from combat-exposed veterans with PTSD(+) (n = 10) and without PTSD(−) (n = 10) were incubated with increasing concentrations (vehicle, 2.5 nM, 5 nM, 50 nM) of dexamethasone (DEX). Across diagnosis and dosage, several genes and gene networks were reliable markers of glucocorticoid stimulation (FDR < 5%), including enhanced expression of FKPB5, VIPR1, NR1I3, and apoptosis-related pathways, and reduced expression of NR3C1, STAT1, IRF1, and related inflammatory and cellular stress-responsive pathways. Dose-dependent differential transcriptional changes in several genes were also identified between PTSD+ and PTSD−. Robust changes in expression were observed at 2.5 nM DEX in PTSD− but not PTSD+ participants; whereas, with increasing concentrations (5 nM and 50 nM), several genes were identified to be uniquely up-regulated in PTSD+ but not PTSD− participants. Collectively, these preliminary findings suggest that genome-wide gene expression profiling of DEX-stimulated PBMCs is a promising method for the exploration of the dynamic differential molecular responses to stress hormones in PTSD, and may identify novel markers of altered glucocorticoid signaling and responsivity in PTSD.

Distinct Profiles of Cell-Free MicroRNAs in Plasma of Veterans with Post-Traumatic Stress Disorder.

Dysregulation of circulating microRNAs (miRNAs) in body fluids has been reported in psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder (PTSD). Recent studies of various diseases showed that extracellular vesicles (EV) in body fluids can provide different spectra of circulating miRNAs and disease-associated signatures from whole fluid or EV-depleted fraction. However, the association of miRNAs in EVs to PTSD has not been studied. In this study, we performed a comprehensive profiling of miRNAs in whole plasma, extracellular vesicles (EV) and EV-depleted plasma (EVD) samples collected from combat veterans with PTSD and matched controls by utilizing a next-generation sequencing (NGS) platform. In total, 520 circulating miRNAs were quantified from 24 male Iraq and Afghanistan combat veterans with (n = 12) and without (n = 12) PTSD. The overall miRNA profiles in whole plasma, EV and EVD fractions were different and miRNAs affected by PTSD were also distinct in each sample type. The concentration changes of miR-203a-3p in EV and miR-339-5p in EVD were confirmed in an independent validation cohort that consisted of 20 veterans (10 with and 10 without PTSD) using qPCR. The target genes of these two miRNAs were involved in signaling pathways and comorbid conditions associated with PTSD (e.g., neurotransmitter systems such as dopaminergic and serotonergic signaling, inflammatory response, and cardiovascular diseases). Our findings suggest that PTSD may have different impacts on miRNAs encapsulated in vesicles and outside of vesicles. Further studies using larger samples are needed to evaluate the utility of these miRNAs as diagnostic biomarkers for PTSD.

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone.

Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%–13% of the general population and 20%–30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABAA receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABAA receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.

Animal models of post-traumatic stress disorder and novel treatment targets.

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.

SA57 - GENETIC AND EPIGENETIC INVOLVEMENT OF THE FKPB5 GENE IN POSTTRAUMATIC STRESS DISORDER AFTER COMBAT TRAUMA

Background FK506 binding protein 5 (FKBP5) is a major regulatory protein of the HPA axis, which binds to the glucocorticoid receptors and modulate glucocorticoid sensitivity. The FKBP5 genes have been implicated in dysregulation of human stress responses, contributing to vulnerable phenotypes such as depression and anxiety. The present study aimed to investigate whether genetic and epigenetic factors of the FKBP5 are a predictive biomarker of Posttraumatic Stress Disorder (PTSD) among veterans exposed to combat. In addition, the influence of potentially associated factors, including combat exposure levels and alcohol problem, was examined in the pathophysiology of PTSD. Methods All subjects were Korean male veterans who served on active duty during the Vietnam War and the Combat Exposure Scale (CES) was used for assessing the level of wartime stressors experienced by combatants. Using the Clinician-Administered PTSD Scale (CAPS), combat veterans were grouped into those with (n=124) and without (n=120) PTSD. Three SNPs of the FKBP5 locus (rs9296158, rs1360780, and rs9470080) were genotyped with single base primer extension assay using the ABI PRISM SNaPShot Multiplex kit. DNA methylation levels at two CpG sites in the FKBP5 intron 7 region were quantified in the peripheral blood using the bisulfite pyrosequencing method. The effects of FKBP5 variants, the DNA methylation levels and clinical factors on the diagnosis of PTSD were tested using binary logistic regression analysis. Results Since a significant interaction effect between alcohol problem and FKBP5 variants was found for PTSD symptom, logistic regression analyses stratified by presence of alcohol problem were performed. Among combat-exposed individuals without alcohol problem, the risk allele of FKBP5 rs1360780, higher methylation levels at the FKBP5 CpG1 site, high combat exposure significantly predicted PTSD diagnosis in combat-exposed individuals (Model Summary: -2 Log likelihood=144.07, Nagelkerke R2=0.279; Overall percentage of correct classification resulting from the model=72.9%). In the logistic model among subjects with alcohol problem, the combat exposure level was an only significant predictor of PTSD status. Discussion The present study demonstrated the involvement of FKBP5 genetic variants and higher DNA methylation of the FKBP5 in PTSD status without alcohol problem. The present findings suggest that the external traumatic events may influence PTSD pathophysiology via genetic and epigenetic modulation of the FKBP5 and alcohol problem may be a moderating factor of PTSD. Further prospective research examining genetic variants and epigenetic changes of FKBP5 locus in people exposed to trauma might shed light on the role and the biological basis of FKBP5 in susceptibility to PTSD.

PTSD Biomarker Database: deep dive metadatabase for PTSD biomarkers, visualizations and analysis tools.

The PTSD Biomarker Database (PTSDDB) is a database that provides a landscape view of physiological markers being studied as putative biomarkers in the current post-traumatic stress disorder (PTSD) literature to enable researchers to explore and compare findings quickly. The PTSDDB currently contains over 900 biomarkers and their relevant information from 109 original articles published from 1997 to 2017. Further, the curated content stored in this database is complemented by a web application consisting of multiple interactive visualizations that enable the investigation of biomarker knowledge in PTSD (e.g. clinical study metadata, biomarker findings, experimental methods, etc.) by compiling results from biomarker studies to visualize the level of evidence for single biomarkers and across functional categories. This resource is the first attempt, to the best of our knowledge, to capture and organize biomarker and metadata in the area of PTSD for storage in a comprehensive database that may, in turn, facilitate future analysis and research in the field.

Epigenetic Meta-Analysis Across Three Civilian Cohorts Identifies NRG1 and HGS as Blood-Based Biomarkers for Post-Traumatic Stress Disorder

Trauma exposure is a necessary, but not deterministic, contributor to post-traumatic stress disorder (PTSD). Epigenetic factors may distinguish between trauma-exposed individuals with versus without PTSD. We conducted a meta-analysis of PTSD epigenome-wide association studies in trauma-exposed cohorts drawn from civilian contexts. Whole blood-derived DNA methylation levels were analyzed in 545 study participants, drawn from the three civilian cohorts participating in the PTSD working group of the Psychiatric Genomics Consortium. Two CpG sites significantly associated with current PTSD in NRG1 (cg23637605) and in HGS (cg19577098). PTSD is associated with differential methylation, measured in blood, within HGS and NRG1 across three civilian cohorts.

Effects of Threat Context, Trauma History, and Posttraumatic Stress Disorder Status on Physiological Startle Reactivity in Gulf War Veterans.

In the current study, we explored exaggerated physiological startle responses in posttraumatic stress disorder (PTSD) and examined startle reactivity as a biomarker of PTSD in a large veteran sample. We assessed heart rate (HR), skin conductance (SC), and electromyographic (EMG) startle responses to acoustic stimuli under low-, ambiguous-, and high-threat conditions in Gulf War veterans with current (n = 48), past (n = 42), and no history of PTSD (control group; n = 152). We evaluated PTSD status using the Clinician-Administered PTSD Scale and trauma exposure using the Trauma History Questionnaire. Participants with current PTSD had higher HR, ds = 0.28-0.53; SC, d = 0.37; and startle responses than those with past or no history of PTSD. The HR startle response under ambiguous threat best differentiated current PTSD; however, sensitivity and specificity analyses revealed it to be an imprecise indicator of PTSD status, ROC AUC = .66. Participants with high levels of trauma exposure only showed elevated HR and SC startle reactivity if they had current PTSD. Results indicate that startle is particularly elevated in PTSD when safety signals are available but a possibility of danger remains and when trauma exposure is high. However, startle reactivity alone is unlikely to be a sufficient biomarker of PTSD.

A Clinician’s Guide to PTSD Biomarkers and Their Potential Future Use

No clinically validated biomarkers have yet been found to assist in the diagnosis and treatment of posttraumatic stress disorder (PTSD). Innovation in clinical trial design, however, has led to the study of biomarkers as part of testing new medications and psychotherapies. There may soon be viable biomarkers to assist in diagnosis of PTSD and prediction of illness trajectory, severity, and functional outcomes; subtyping; and treatment selection. Processes for the identification and validation of biomarker findings are complex, involving several stages of clinical testing before use. The authors provide an overview of issues regarding the clinical use of PTSD biomarkers and examine a set of genetic, epigenetic, and other blood-based markers along with physiological markers currently proposed as candidate tests for PTSD. Studies that have identified candidate biomarkers with relevance to treatment selection in PTSD are discussed as a promising area of research that may lead to changes in clinical practice.

The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans

Previous research indicates that interactions between FKBP5 single nucleotide polymorphisms (SNPs) and child abuse are associated with posttraumatic stress disorder (PTSD) in adulthood. We examined the relationship between the T-allele of the rs1360780 FKBP5 SNP and child abuse on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Genotyping was completed on 266 veterans and 174 veterans additionally participated in a low dose dexamethasone suppression test (DST). The CAPS was used to determine PTSD status and the THQ was used to determine child abuse operationalized as either childhood physical or sexual abuse. Hierarchical regression models were used to assess FKBP5 × child abuse interactions on PTSD, basal cortisol levels, and post DST cortisol levels. The FKBP5 risk allele and child abuse were separately associated with PTSD diagnosis. The risk allele was also associated with significantly lower cortisol levels at baseline. However, no significant FKBP5 × child abuse interaction on PTSD diagnosis, basal cortisol levels, or greater cortisol suppression was observed. Our results suggest that FKBP5 may be a viable biomarker for PTSD. Nonetheless, further work will be required to reconcile our findings with previous reports of an FKBP5 × child abuse interaction on posttraumatic stress response.

A Systematic Review of Interleukin-1β in Post-Traumatic Stress Disorder: Evidence from Human and Animal Studies

Pro-inflammatory cytokines, such as interleukin (IL)-1β, have been implicated as underlying pathophysiological mechanisms and potential biomarkers of post-traumatic stress disorder (PTSD). This systematic review examines data regarding IL-1β production/concentration in human and animal studies of PTSD. In accordance with PRISMA guidelines, relevant articles from PubMed were reviewed from inception until July 10, 2017. Nineteen studies were eligible for inclusion. Animal studies demonstrated increased hippocampal IL-1β in rodent models of PTSD. Several immunomodulatory drugs were shown to reduce elevated IL-1β levels and anxiety-like behaviors in animals. Human cross-sectional studies showed contradictory results; serum and plasma IL-1β concentrations in PTSD patients were either elevated or did not differ from control groups. In vitro IL-1β production by stimulated cells demonstrated no difference between PTSD and control participants, although spontaneous in vitro production of IL-1β was increased in the PTSD group. The findings from 2 longitudinal studies were inconsistent. Given the conflicting findings, it is premature to consider IL-1β as a biomarker of PTSD. Anti-inflammatory agents may reduce IL-1β, and be a potential basis for future therapeutic agents in PTSD treatment. More longitudinal research is needed to better understand the role of IL-1β in the development and/or maintenance of PTSD.

Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder

Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder

Upregulation of the Ribosomal Pathway as a Potential Blood-Based Genetic Biomarker for Comorbid Major Depressive Disorder (MDD) and PTSD

Major Depressive Disorder (MDD), and Post-Traumatic Stress Disorder (PTSD) are two of the fastest growing comorbid diseases in the world. A patient without any genetic predisposition to depression can live a healthy lifestyle but develop depression as a result of their environment, such as the occurrence of a traumatic event. This study addresses the question of whether there are any biomarkers in blood that could alert physicians of a patient’s susceptibility to comorbid MDD and PTSD. Since the pathophysiology of comorbid MDD is complex, it has been hypothesized that there could be several gene groups acting as biomarkers. Based on existing literature, the genes DICER1, FK506, and MRPS23 are thought to be relevant biomarkers. Using GEO2R, provided by NCBI, we conducted a differential gene expression analysis. We used patient dataset GSE67663, which contained 184 blood samples, including 72 control samples and 112 test samples. The top 253 genes that had p-values from 1.6 x 10^-6 to 3.49 x 10^3 were entered into the STRING database in order to identify common protein interactions. In accordance with the KEGG Ribosomal Pathway, two main gene groups, including those involved in mitochondrial ribosomal translation, were further analyzed for common gene ontology and biological processes. In the end, we found that the Ribosomal Pathway (ID: 03010) contained 29 upregulated genes and is a potential blood-based biomarker. This study has applications to the field of personalized medicine, in which tailored treatments based on biomarkers and one’s genome are utilized to identify people at risk for disease.

A Systematic Review of Tumor Necrosis Factor-α in Post-Traumatic Stress Disorder: Evidence from Human and Animal Studies.

Growing evidence suggests a pathophysiological role of cytokines in post-traumatic stress disorder (PTSD). Tumor necrosis factor (TNF)-α is a key cytokine. Therefore, we performed a systematic review to examine the findings regarding TNF-α derived from both animal and human studies of PTSD. Using PRISMA guidelines, we reviewed relevant articles in PubMed from inception until 11th April 2017. Human studies that reported group comparisons and/or longitudinal investigations of TNF-α production/concentration were included. Research reporting on TNF-α levels in animal models of PTSD were also included. Twenty-seven articles were identified. Data from human cross-sectional studies suggests that plasma/serum levels of TNF-α are elevated in those with PTSD, as compared to healthy controls. Longitudinal assessments of TNF-α are limited and data are mixed. Limited data from animal studies suggest an increased TNF-α production in the hippocampus of rats following stress, which can be reversed by immunomodulatory drugs. Our findings suggest TNF-α may be a potential biomarker and treatment target for PTSD. Findings need to be considered in light of heterogeneous methods for measurement and analysis of TNF-α concentration. Longitudinal research is needed to understand the role of TNF-α in the development and/or maintenance of PTSD.

A Functional Near-Infrared Spectroscopy Study of Trauma-Related Auditory and Olfactory Cues: Posttraumatic Stress Disorder or Combat Experience?

The prevalence of posttraumatic stress disorder (PTSD) among U.S. veterans deployed to Iraq or Afghanistan necessitates the need for comprehensive assessment and treatment strategies. This study investigated the utility of a combat-related PTSD symptom provocation paradigm to elicit unique neurological responses across three groups: combat veterans with PTSD, combat veterans without PTSD, and nonmilitary participants without PTSD. Using functional near-infrared spectroscopy (fNIRS) the results indicated that combat veterans with PTSD demonstrated significant activation to a trauma-related sound compared with nonmilitary personnel, channel 14: d = 1.03, 95% confidence interval (CI) [0.28, 1.76]; channel 15: d = 1.30, 95% CI [0.53, 2.06]; and combat veterans without PTSD, channel 14: d = 0.87, 95% CI [0.14, 1.59]. Specifically, this increased neural activation was approximately located in the right medial superior prefrontal cortex (Brodmann areas 9/10), an area associated with experiencing negative or threatening stimuli and emotional detachment. There were no differences across the groups for nontrauma-related sounds. Results were less clear with respect to a combat-related odor. These results suggest a specific neurophysiological response to trauma-related cues and, if replicated, may offer a biomarker for combat-related PTSD. Such a response could provide incremental validity over diagnostic assessments alone and assist in planning and monitoring of treatment outcome.

Alcohol Use Disorder Moderates the Effect of Age on Heart Rate Variability in Veterans With Posttraumatic Stress Disorder.

Research on heart rate variability (HRV) in posttraumatic stress disorder (PTSD) and comorbid alcohol use disorder (AUD) is limited despite its use as a biomarker of both disorders. This study examined whether AUD comorbidity contributes an additive effect on HRV for veterans with PTSD. HRV was assessed in 70 male Operation Enduring Freedom/Operation Iraqi Freedom veterans with PTSD, including 32 with co-occurring AUD. Mean HRV values for both groups were below the mean for healthy adults, but additive effects of PTSD and AUD on HRV were not observed. Consistent with prior studies, hierarchical regressions showed that HRV decreased with age in the PTSD-only group. However, HRV increased slightly with age among veterans with both PTSD and AUD. This interaction remained significant after controlling for common HRV covariates. These findings support HRV as a biomarker of PTSD and extend research by demonstrating the complex relationship between PTSD and HRV in the context of co-occurring AUD.

Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume

Smaller hippocampal volume has been consistently observed as a biomarker of posttraumatic stress disorder (PTSD). However, less is known about individual volumes of the subfields composing the hippocampus such as the dentate gyrus and cornu ammonis (CA) fields 1–4 in PTSD. The aim of the present study was to examine the hypothesis that volume of the dentate gyrus, a region putatively involved in distinctive encoding of similar events, is smaller in individuals with PTSD versus trauma-exposed controls. Ninety-seven recent war veterans underwent structural imaging on a 3T scanner and were assessed for PTSD using the Clinician-Administered PTSD Scale. The hippocampal subfield automated segmentation program available through FreeSurfer was used to segment the CA4/dentate gyrus, CA1, CA2/3, presubiculum, and subiculum of the hippocampus. Results showed that CA4/dentate gyrus subfield volume was significantly smaller in veterans with PTSD and scaled inversely with PTSD symptom severity. These results support the view that dentate gyrus abnormalities are associated with symptoms of PTSD, although additional evidence is necessary to determine whether these abnormalities underlie fear generalization and other memory alterations in PTSD.

Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD.

Epigenetic modifications such as DNA methylation may play a key role in the aetiology and serve as biomarkers for post-traumatic stress disorder (PTSD). We performed a genomewide analysis to identify genes whose DNA methylation levels are associated with PTSD. A total of 211 individuals comprising Australian male Vietnam War veterans (n = 96) and males from a general population belonging to the Grady Trauma Project (n = 115) were included. Genomewide DNA methylation was performed from peripheral blood using the Illumina arrays. Data analysis was performed using generalized linear regression models. Differential DNA methylation of 17 previously reported PTSD candidate genes was associated with PTSD symptom severity. Genomewide analyses revealed CpG sites spanning BRSK1, LCN8, NFG and DOCK2 genes were associated with PTSD symptom severity. We replicated the findings of DOCK2 in an independent cohort. Pathway analysis revealed that among the associated genes, genes within actin cytoskeleton and focal adhesion molecular pathways were enriched. These data highlight the role of DNA methylation as biomarkers of PTSD. The results support the role of previous candidates and uncover novel genes associated with PTSD, such as DOCK2. This study contributes to our understanding of the biological underpinnings of PTSD.

The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/ MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1β is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy.

Epigenetic alterations of the BDNF gene in combat-related post-traumatic stress disorder.

Brain-derived neurotrophic factor (BDNF) plays a crucial role in modulating resilience and vulnerability to stress. The aim of this study was to investigate whether epigenetic regulation of the BDNF gene is a biomarker of post-traumatic stress disorder (PTSD) development among veterans exposed to combat in the Vietnam War. Using the Clinician-Administered PTSD Scale, combat veterans were grouped into those with (n = 126) and without (n = 122) PTSD. DNA methylation levels at four CpG sites within the BDNF promoter I region were quantified in the peripheral blood using pyrosequencing. The effects of BDNF DNA methylation levels and clinical variables on the diagnosis of PTSD were tested using binary logistic regression analysis. Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD. High methylation levels at the BDNF promoter CpG site, high combat exposure, and alcohol problems were significantly associated with PTSD diagnosis. This study demonstrated an association between higher DNA methylation of the BDNF promoter and PTSD diagnosis in combat-exposed individuals. Our findings suggest that altered BDNF methylation may be a valuable biomarker of PTSD after trauma exposure.