Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration–approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution. Methods: Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males)and 21 healthy demographically comparable controls (15 females, 6 males)to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents. Findings: The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms. Implications: The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation–based treatment strategies.