Mary G Jeffrey1, Lubov Nathanson2, Kristina Aenlle3, Zachary M Barnes4, Mirza Baig5, Gordon Broderick6, Nancy G Klimas7, Mary Ann Fletcher3, Travis J A Craddock8. 1. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA. 2. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA. 3. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Miami Veterans Affairs Medical Center, Miami, FL, USA. 4. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; Miami Veterans Affairs Medical Center, Miami, FL, USA; Miller School of Medicine, University of Miami, Miami, FL, USA; Diabetes Research Institute, University of Miami, Miami, FL, USA. 5. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA. 6. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Center for Clinical Systems Biology, Rochester General Hospital, Rochester, NY, USA. 7. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA. 8. Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Clinical Immunology, Nova Southeastern University, Ft. Lauderdale, FL, USA; Department of Computer Science, Nova Southeastern University, Ft. Lauderdale, FL, USA. Electronic address: tcraddock@nova.edu.
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 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.
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, tumornecrosis 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.
Authors: Melanie Perez; Rajeev Jaundoo; Kelly Hilton; Ana Del Alamo; Kristina Gemayel; Nancy G Klimas; Travis J A Craddock; Lubov Nathanson Journal: Front Pediatr Date: 2019-05-24 Impact factor: 3.418
Authors: Amanpreet K Cheema; Laura E Wiener; Rebecca B McNeil; Maria M Abreu; Travis Craddock; Mary A Fletcher; Drew A Helmer; J Wesson Ashford; Kimberly Sullivan; Nancy G Klimas Journal: Life Sci Date: 2021-07-10 Impact factor: 6.780
Authors: Amanpreet K Cheema; Leonor Sarria; Mina Bekheit; Fanny Collado; Eloy Almenar-Pérez; Eva Martín-Martínez; Jose Alegre; Jesus Castro-Marrero; Mary A Fletcher; Nancy G Klimas; Elisa Oltra; Lubov Nathanson Journal: J Cell Mol Med Date: 2020-04-14 Impact factor: 5.310
Authors: João Malato; Franziska Sotzny; Sandra Bauer; Helma Freitag; André Fonseca; Anna D Grabowska; Luís Graça; Clara Cordeiro; Luís Nacul; Eliana M Lacerda; Jesus Castro-Marrero; Carmen Scheibenbogen; Francisco Westermeier; Nuno Sepúlveda Journal: Heliyon Date: 2021-07-29