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

Purpose: 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.