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Chronic inflammation is a key factor in symptomology and comorbidities of post-traumatic stress disorder (PTSD). Levels of a proinflammatory marker, C-reactive protein (CRP) are increased in individuals with PTSD but it is not clear if this is due to trauma exposure or PTSD. Our study aimed to assess the relationship between serum CRP levels, CRP SNPs, methylation, mRNA expression and PTSD in a homogenous trauma exposed Australian Vietnam veteran cohort. We hypothesized that decreased DNA methylation would be associated with increased gene expression and increased peripheral CRP levels in PTSD patients and that this would be independent of trauma. Participants were 299 Vietnam veterans who had all been exposed to trauma and approximately half were diagnosed with PTSD. We observed higher levels of serum CRP in the PTSD group compared to the non-PTSD group but after controlling for BMI and triglycerides the association did not remain significant. No association was found between CRP SNPs and PTSD or CRP levels. Absent in Melanoma 2 (AIM2) which is a mediator of inflammatory response and a determinant of CRP levels was analysed for DNA methylation and mRNA expression. We observed a trend level association between PTSD and AIM2 methylation after controlling for age, smoking, triglycerides, BMI and cell types. There was no significant interaction between PTSD and CRP levels on AIM2 methylation after controlling for covariates. We observed that as AIM2 methylation levels decreased, AIM2 mRNA expression increased. Elevated CRP levels were associated with AIM2 mRNA in the trauma exposed cohort but there was no significant interaction effect with PTSD. Our results could not confirm that CRP is a marker of PTSD independent of trauma in this group of older veterans. CRP may be a broad marker of disease risk, or a marker of PTSD in younger cohorts than those in this study.

Brain-derived neurotrophic factor (BDNF) gene is associated with increased risk of posttraumatic stress disorder (PTSD) and plays a role in neuroplasticity, cognition and memory. BDNF has strong potential as a therapeutic target as studies have shown that antidepressants, electroconvulsive treatment and exercise modulate BDNF expression and methylation. In this study we examined the role of BDNF methylation and expression in PTSD and the implications of exercise in mediating these effects. BDNF DNA methylation and gene expression analysis was performed in a sample of 96 male Vietnam veterans. Cases were combat-exposed veterans with current PTSD (n = 48) and controls were combat exposed veterans with no past or current PTSD diagnosis (n = 48). No association between BDNF mRNA and PTSD was identified. PTSD was associated with decreased methylation at three BDNF CpG sites (cg01546433 P = 0.004835; cg24650785 P = 0.000259 and cg002298481 P = 0.000672). Differential BDNF methylation was associated with exercise, with active exercise associated with lower methylation levels at three CpG sites (cg04481212 P = 0.005; cg01546433 P = 0.025 and cg00298481 P = 0.035). Given that exercise mediates BDNF action on cognitive plasticity, exercise may be a non-invasive, drug free option in the treatment of PTSD.

The nitric oxide pathway in the hippocampus is involved in the biological stress response with detrimental consequences to cells and HPA axis feedback. Hippocampal atrophy and HPA axis feedback dysfunction are associated with posttraumatic stress disorder (PTSD). This study systematically investigates two genes of the nitric oxide pathway NOS1AP and NOS1 for a potential involvement in PTSD, comorbidities and resilience. A cohort of age and gender matched Vietnam veterans including trauma-exposed cases and controls was recruited and comprehensively assessed (n = 299). A total of 49 NOS1AP and 16 NOS1 polymorphisms were analysed and genotypes correlated with gold standard clinical measures to assess PTSD severity and related phenotypes (depression, anxiety, stress, resilience) based on diagnostic status. Multiple NOS1AP polymorphisms were associated across all measures, and NOS1 polymorphisms were associated with PTSD severity, stress and resilience. The GG genotype of NOS1 polymorphism rs10744891 was associated with PTSD severity (surviving multiple correction) while the combined TT-TG genotypes were associated with resilience (p = 0.005; p = 0.033, respectively). This study indicates that NOS1AP and NOS1 from the nitric oxide pathway are likely to play a key role in PTSD, its comorbidities and resilience. Given the essential role of NOS1AP and NOS1 in stress response they may be reliable targets for screening and intervention strategies.