Associations Between Circulating Inflammatory Cytokines and Neuropathic Pain: A Two-Sample Mendelian Randomization Study

Yihan Zheng,1 Hongmei Wang,2 Huale Zhang,3 Xizhu Wu,1 Min Zhou,1 Wang Denggui1 1Department of Anesthesiology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 2Department of Breast Surgery, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 3Department of Obstetrics, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of ChinaCorrespondence: Wang Denggui, Department of Anesthesiology, Fujian Maternity and Child Health Hospital, No. 18 Daoshan Road, Fuzhou City, Fujian Province, 350001, People’s Republic of China, Tel +86-0591-15980289738, Email [email protected]: Several recent observational studies have reported that the circulating inflammatory cytokine composition is associated with neuropathic pain. However, the causal effect of 41 circulating inflammatory cytokines on neuropathic pain is unknown.Patients and Methods: A two-sample Mendelian randomization study was performed using summary statistics for a genome-wide association study (GWAS) of circulating inflammatory cytokines conducted within three Finnish cohorts (YFS and FINRISK 1997 and 2002, n=8,293). The summary statistics of neuropathic pain were obtained from the GWAS dataset (800 patients and 195,047 controls). Inverse variance weighting, weighted median weighting, MR‒Egger regression, simple weighting, and weighted weighting were used to examine the causal associations between inflammatory cytokines and neuropathic pain. Sensitivity analyses, including the Cochran Q test, Egger intercept test, and leave-one-out analysis, were performed to verify the robustness of the MR results.Results: Inverse variance weighted estimates suggested that G-CSF (OR=0.57, 95% CI=0.39– 0.83, P=3.4e− 03), IL-16 (OR=0.73, 95% CI=0.55– 0.96, P=2.7e− 02), and IL-1β (OR=0.57, 95% CI=0.33– 0.99, P=4.4e− 02) had protective effects on neuropathic pain. In addition, IP-10 (OR=1.36, 95% CI=1.06– 1.74, P=1.5e− 02) was suggested to be associated with neuropathic pain. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found.Conclusion: This two-sample Mendelian randomization study revealed that G-CSF, IL-16, IL-1β, and IP-10 were causally associated with neuropathic pain. This knowledge could guide future research in developing more effective treatments for neuropathic pain, potentially leading to better pain management options for patients.Keywords: neuropathic pain, inflammatory cytokines, Mendelian randomization, genome-wide association study, pain management