Improved Sleep in Military Personnel is Associated with Changes in the Expression of Inflammatory Genes and Improvement in Depression Symptoms

Abstract

Study objectivesSleep disturbances are common in military personnel and are associated with increased risk for psychiatric morbidity, including posttraumatic stress disorder (PTSD) and depression, as well as inflammation. Improved sleep quality is linked to reductions in inflammatory bio-markers; however, the underlying mechanisms remain elusive.MethodsIn this study, we examine whole genome expression changes related to improved sleep in 68 military personnel diagnosed with insomnia. Subjects were classified into the following groups and then compared: improved sleep (n = 46), or non-improved sleep (n = 22) following three months of standard of care treatment for insomnia. Within subject differential expression was determined from microarray data using the Partek Genomics Suite analysis program and the ingenuity pathway analysis (IPA) was used to determine key regulators of observed expression changes. Changes in symptoms of depression and PTSD were also compared.ResultsAt baseline, both groups were similar in demographics, clinical characteristics, and gene-expression profiles. The microarray data revealed that 217 coding genes were differentially expressed at the follow-up-period compared to baseline in the participants with improved sleep. Expression of inflammatory cytokines were reduced including IL-1β, IL-6, IL-8, and IL-13, with fold changes ranging from −3.19 to −2.1, and there were increases in the expression of inflammatory regulatory genes including toll-like receptors 1, 4, 7, and 8 in the improved sleep group. IPA revealed six gene networks, including ubiquitin, which was a major regulator in these gene-expression changes. The improved sleep group also had a significant reduction in the severity of depressive symptoms.ConclusionInterventions that restore sleep likely reduce the expression of inflammatory genes, which relate to ubiquitin genes and relate to reductions in depressive symptoms.

Genetic Pathways to Insomnia

“…One gene in particular, Urotensin 2, was significantly down regulated, and represents a potential insomnia target, given its role in orexin regulation and rapid eye movement. Another study by the same group investigated gene expression changes in military personnel with insomnia, focusing on differences between individuals who did or did not experience improvements in sleep following three months of insomnia treatment [94]. Positive changes in immune-related genes (i.e., lower expression of inflammatory cytokines, increases in regulatory genes), implication of the ubiquitin pathway (via pathway analysis) and improvement in depression symptoms were all seen in the improved sleep group, providing insight into the molecular changes that occur with successful insomnia interventions.…”

Biological and clinical insights from genetics of insomnia symptoms

“…Partitioning of heritability across tissue types 25,26 showed enrichment in the central nervous system, adrenal/pancreas tissue lineages and skeletal muscle (p<10 -5 ) (Supplementary Table 17 [29][30][31][32] . Furthermore, the restless legs syndrome gene BTBD9 has been implicated as a substrate adaptor for the Cullin-3 class of E3 ubiquitin ligases 33 .…”

National Institutes of Health Symptom Science Model sheds light on patient symptoms

“…This gene has been associated with switching between different stages of sleep, which may in turn be the mechanism underlying insomnia symptoms (Gill, et al, 2015). Further, in another study, Dr. Gill’s team found that for patients whose sleep improved, inflammatory genes were expressed differently compared to their own baseline expression, and, that the differential expression was also related to reductions in depression symptoms (Livingston, et al, 2015). These studies show that differential gene-expression relates to insomnia and chronic symptoms in military personnel, and that standard care can change gene-activity.…”