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Sex-specific transcriptional differences in Gulf War Illness patients under stressful conditions

ABSTRACT: Background Gulf War Illness (GWI) is a severely debilitating condition with chronic symptoms affecting up to 30% of the veterans deployed to the 1990-91 Persian Gulf War. The symptoms associated with GWI include fatigue, musculoskeletal/joint pain and disturbances of multiple organ systems. The mechanisms of GWI are unknown, although the symptoms suggest that GWI is most likely caused by a combination of genetic predisposition and it’s interaction with environmental factors such as exposure to toxic chemicals. Objectives This research project aims to assess how sex differences in individuals with GWI impact their response to stress, specifically through an exercise challenge. Additionally, it highlights the importance of considering sex differences in the diagnosis and treatment of GWI. Methods We utilized RNA-seq to examine the differential gene expression (GE) in peripheral blood mononuclear cells of 24 female GWI patients, 20 male GWI patients, and 40 healthy controls (HC) who were matched in for sex, age, and BMI. We evaluated the gene expression changes at three time points: T0 (baseline), T1 (at maximal exertion), and T2 (4 hours into recovery after T1). To ensure consistency, we excluded genes located on the sex chromosomes and performed separate analyses for men and women. Our focus was to compare the response to exercise within each group (GWI patients and HC) between different time points. Results In the male GWI cohort, pathways associated with immune system process, particularly IL-12, and natural killer cell cytotoxicity were activated during exercise. The female GWI patients exhibited less significant changes in gene expression than men. During the recovery period, male GWI patients demonstrated distinct alterations in the regulation of innate immune responses. On the other hand, female GWI patients showed significant changes in genes related to regulation of intracellular signal transduction. These functional pathways and differentially expressed genes identified in this project provide valuable insights into the sex-specific pathophysiology of GWI. Conclusion The identification of sex-specific biomarkers and therapeutic targets in GWI holds great potential for understanding the distinct onset and progression of this disease in different sexes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286345 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.

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Sex-specific transcriptional differences in Gulf War Illness patients under stressful conditions

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