Source: Clinical Therapeutics Preprint Date: March 6, 2019 URL: https://www.sciencedirect.com/science/article/abs/pii/S0149291819300475 Treatment avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A split-gender pharmacogenomic study of gene-expression modules ---------------------------------------------------------- Mary G. Jeffrey(1,2), Lubov Nathanson(1,3), Kristina Aenlle(1,3,4), Zachary M. Barnes(1,4,5,6), Mirza Baig(1), Gordon Broderick (1,2,3,7,8), Nancy G. Klimas(1,2,3), Mary Ann Fletcher(1,3,4), Travis J.A. Craddock(1,2,3,9,*) 1 Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA 2 College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA 3 Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA 4 Miami Veterans Affairs Medical Center, Miami, FL, USA 5 Miller School of Medicine, University of Miami, Miami, FL, USA 6 Diabetes Research Institute, University of Miami, Miami, FL, USA 7 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada 8 Center for Clinical Systems Biology, Rochester General Hospital, Rochester, NY, USA 9 Department of Computer Science, Nova Southeastern University, Ft. Lauderdale, FL, USA * Corresponding author. Institute for Neuro-Immune Medicine, Nova Southeastern University, 3301 College Avenue, Fort Lauderdale, FL 33314, USA. Email: email@example.com Received 7 November 2018 Revised 9 January 2019 Accepted 18 January 2019 Available online 6 March 2019. Abstract 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 delta<0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor alpha, transforming growth factor beta, 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. (Clin Ther. 2019;41:XXX-XXX) (c) 2019 Elsevier Inc.