Reductions in Symptom Severity of Posttraumatic Stress Disorder is Associated with Reduced Expression of Inflammatory Genes in Service Members

Background: Posttraumatic stress disorder (PTSD) is common and increases morbidity risk in affected service members (SMs) returning from deployment, with even greater risk when depression is comorbid. Inflammation is implicated in PTSD and is linked to morbidity risks; however, the role of gene-activity and relation to inflammation in PTSD recovery is not well understood. Presumably PTSD recovery reverses the morbidity risks related to inflammation and other gene-networks, which would have great implications to the health and well-being of military personnel with PTSD.

Purpose: To determine gene-activity changes related to changes in severity of PTSD and depression symptoms in SMs who recently returned from deployment, using peripheral blood trasncriptome profiling.

Methods: Symptoms of PTSD and depression were determined using the PTSD Checklist Military Version (PCL-M) and the Quick Inventory of Depressive Symptomatology (QIDS) , respectively, in a sample of 85 male SMs (mean age 33.7 years; 69.4% White) within 12 months of deployment (baseline) who were also re-evaluated at 3 months follow-up. Symptom severity groups were determined by increase, decrease, or no change in symptoms at 3 months as compared to baseline. RNA samples from peripheral blood drawn at baseline and 3 months were tested on Affymetrix GeneChip HG-U133 Plus 2.0 Array platform. Differential gene expression was determined among the 3 PTSD symptom severity groups (increase, decrease, or no change), and the 3 depression symptom severity groups (increase, decrease, or no change). P-values were corrected for multiple comparisons using false discovery rate (FDR < 0.05). Transcripts were validated by qPCR.

Results: SMs in the decreased PTSD symptom severity group at 3 months had significant reductions in the expression levels of a number of genes including inflammatory genes, as compared to the “no change” PTSD symptom group. Network analysis of the gene set specific to PTSD symptoms reductions revealed that cell death and survival is the top gene-network, and that NFκB is the hub gene for the mostly down-regulated genes. The most significant canonical pathways for reduced PTSD symptoms include Cdc42, ERK5, HGF, CNTF, and NGF signaling pathways, with glucocorticoid receptor and B cell receptor signaling pathways being implicated in the majority of these pathways. The depression symptom severity groups were found to have no significant association with levels of gene expression.

Conclusions: Our results suggest that reductions in severity of PTSD symptoms are significantly related to genes that are reduced in expression, and that inflammatory genes play a dominant role in these gene-activity changes. Reductions in PTSD symptoms also contribute to signal pathways that regulate cellular responses to stress, neurotrophic growth factors, and other growth factors. Further studies are warranted to discover genes specific to depression symptom severity and its interaction with PTSD, and how these molecular changes may relate to long-term morbidity risks related to PTSD.