Association of Inflammatory Proteins with Neuropathic Pain: A Two-Sample Bidirectional Mendelian Randomization

Object: Previous studies have found that circulating inflammatory proteins may play an essential role in the occurrence and development of neuropathic pain. However, the majority of existing evidence is derived from observational studies, which are prone to confounding factors and reverse causality, and the inflammatory profiles associated with different types of neuropathic pain remain poorly understood. Consequently, more robust methodologies are urgently required to elucidate the causal relationships between these variables. Therefore, a bidirectional Mendelian randomization analysis was performed to assess the causal relationship between inflammatory proteins and neuropathic pain, specifically focusing on neuralgia and neuritis, including glossopharyngeal neuralgia, phantom limb syndrome with pain,small fiber neuropathy, and unspecified neuralgia. Methods: Instrumental variables were obtained from publicly available genome-wide association study datasets. Five different models were used for MR Analysis, including the inverse variance weighted model, weighted median estimation model, weighted model-based method, MR-Egger regression model and simple mode. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers test. Sensitivity analysis was conducted through leave-one-out analysis. Results: The results suggest a genetically predicted potential association between fractalkine levels (CX3CL1) (OR=0.182; 95CI=0.048-0.691; p=0.012), signaling lymphocytic activation molecule levels (SLAMF1) (OR=0.295; 95CI=0.099-0.879; p=0.028), tumor necrosis factor levels (TNF) (OR=0.281; 95CI=0.085-0.931; p=0.038), matrix metalloproteinase-1 (MMP-1) (OR=3.399; 95CI=1.140-10.133; p=0.028), and tumor necrosis factor receptor superfamily member 9 levels (TNFRSF9) (OR=0.281; 95CI=0.085-0.931; p=0.038) with the risk of glossopharyngeal nerve disease. In addition, we identified FGF5, FGF21, FGF23, Osteoprotegerin, CD40LG, IL-12B, IL-20RA, IL-24, CCL8, CCL28, CD244, CCL3, OSM, and SIRT2 as associated with the occurrence of the other three types of neuropathic pain.The sensitivity analysis revealed no heterogeneity or levels of pleiotropy. Conclusion: Our Mendelian randomization analysis revealed several genetically predicted associations between circulating inflammatory proteins and the risk of neuropathic pain subtypes. These findings indicate that immune- and inflammation-related pathways may be implicated in the pathogenesis of neuropathic pain, although further functional and clinical investigations are required to validate these associations and elucidate the underlying mechanisms.