Evaluating the Causal Role of Genetically Inferred Immune Cells and Inflammatory Cytokines on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

<b>Background/Objectives</b>: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted and diverse disorder with an ambiguous etiology. Recent evidence indicates that immune system impairment and inflammatory mechanisms are pivotal to the initiation and advancement of ME/CFS. Nonetheless, the causal relationships among these factors remain inadequately comprehended. <b>Methods</b>: This study investigated the causative contributions of immunological dysfunction and inflammatory variables in ME/CFS utilizing genome-wide association study (GWAS) data. We employed Mendelian randomization (MR) to investigate associations between 91 inflammatory cytokines, 731 immune cell characteristics, and the risk of ME/CFS. Summary statistics for immune cell traits and inflammatory cytokines were sourced from European GWAS cohorts (n = 3757 and n = 14,824, respectively), while ME/CFS data were obtained from the UK Biobank (n = 462,933, including 2076 cases). We predominantly employed the inverse variance weighted (IVW) approach, complemented by MR-Egger, weighted median, BWMR, and MR-RAPS tests to guarantee robust and precise outcomes. <b>Results</b>: The study revealed significant causal links between various inflammatory factors, immune cell characteristics, and the risk of ME/CFS. Increased CXCL5 and CCL20 levels were significantly linked to a higher risk of ME/CFS, while elevated TNF levels were inversely related to ME/CFS risk. Furthermore, 13 immune cell characteristics were identified as having substantial causal associations with the likelihood of ME/CFS. These data are supportive of the causality that immune system dysfunction and inflammatory variables play a pivotal role in the development of ME/CFS. <b>Conclusions</b>: This study provides new insights into the causal role of immune system dysfunction in the development of ME/CFS, contributing to a deeper understanding of its underlying mechanisms. These results offer a foundation for identifying diagnostic biomarkers and developing targeted therapeutic strategies. Future research should validate these findings using multi-center cohort studies and further investigate the mechanisms behind key factors to enable the development of personalized treatment approaches.