Novel Insights Into the Role of Immune Cells and Plasma Metabolites in Fibromyalgia: A Two‐Sample Mendelian Randomization and Mediation Analysis

Introduction Fibromyalgia (FM) is a complex chronic pain disorder of indeterminate etiology. This study aimed to investigate the potential causative effects of immune‐related factors and plasma metabolites on the development of FM using Mendelian randomization (MR) analysis. Methods This research used two‐sample MR analysis was performed using summary data from comprehensive genome‐wide association studies. Genetic instruments were selected for immune cell traits and plasma metabolites. The causal effects on FM risk were estimated, followed by a two‐step MR analysis to assess the mediating pathways. Results Eight immune cell types, including CD8 bright NKT %T cells and CD45 expression on HLA‐DR + NK cells, were recognized as possible risk factors for FM. In contrast, 11 phenotypes, including CD28 expression on CD39 + resting Treg cells and CD3 expression on CD39 + CD4 + cells, demonstrated potential protective effects. In addition, 55 plasma metabolites were causally associated with FM, implicating pathways involved in neuroendocrine regulation, inflammation, lipid metabolism, and energy homeostasis. Two‐step MR further revealed that 5‐hydroxyindole sulfate partially mediated the effect of CD8 bright NKT cell %T on FM risk. Conclusions This study provides novel evidence for the immunological and metabolic mechanisms underlying FM. Recognizing specific immune characteristics and metabolites as causal or mediating elements aids in the development of focused diagnostic and treatment approaches for FM.