Functional investigation and two-sample Mendelian randomization study of neuropathic pain hub genes obtained by WGCNA analysis

OBJECTIVE: Neuropathic pain as a complex chronic disease that occurs after neurological injury, however the underlying mechanisms are not clarified in detail, hence therapeutic options are limited. The purpose of this study was to explore potential hub genes for neuropathic pain and evaluate the clinical application of these genes in predicting neuropathic pain. METHODS: Differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) was used to explore new neuropathic pain susceptibility modules and hub genes. KEGG and GO analyses was utilized to explore the potential role of these hub genes. Nomogram model and ROC curves was established to evaluate the diagnostic efficacy of hub genes. Additionally, the correlation of IL-2 with immune infiltration was explored. Finally, a Mendelian randomization study was conducted to determine the causal effect of IL-2 on neuropathic pain based on genome-wide association studies. RESULTS: WGCNA was performed to establish the networks of gene co-expression, screen for the most relevant module, and screen for 440 overlapping WGCNA-derived key genes. GO and KEGG pathway enrichment analyses demonstrated that the key genes were correlated with cytokine receptor binding, chemokine receptor binding, positive regulation of JAK–STAT cascade, chemokine-mediated signaling pathway, PI3K-AKT pathway and chemokine pathway. Through Cytoscape software, top ten up-regulated genes with high scores were IL2, SMELL, CCL4, CCR3, CXCL1, CCR1, HGF, CXCL2, GATA3, and CRP. In addition, nomogram model performed well in predicting neuropathic pain risk, and with the ROC curve, the model was showed to be effective in diagnosis. Finally, IL2 was selected and we observed that IL2 was causally associated with immune cell infiltrates in trigeminal neuralgia. In inverse variance weighting, we found that IL2 was associated with the risk of trigeminal neuralgia with an OR of 1.203 (95% CI = 1.004–1.443, p = 0.045). CONCLUSION: We constructed a WGCNA-based co-expression network and identified neuropathic pain-related hub genes, which may offer further insight into pre-symptomatic diagnostic approaches and may be useful for the study of molecular mechanisms for understanding neuropathic pain risk genes.