Exploring the Causal Relationship Between Inflammatory Cytokines and Joint Pain: A Mendelian Randomization Study

Joint pain is a major cause of chronic disability worldwide, with complex mechanisms and limited treatment options. Inflammatory cytokines have been implicated in the pathogenesis of joint pain; however, their causal roles remain unclear. This study employed Mendelian randomization (MR) to explore the causal relationships between 41 inflammatory cytokines and the risk of joint pain.

We integrated genome-wide association study (GWAS) summary statistics from European-ancestry populations, including data on joint pain (1451 cases and 461,559 controls) and inflammatory cytokine levels (8293 Finnish participants). Genetic variants meeting instrumental variable assumptions (p < 1 × 10^-5) were selected. Causal estimates were derived using inverse-variance weighted (IVW), weighted median, and MR-Egger regression. Sensitivity analyses incorporated Cochran's Q test, MR-Egger intercept analysis, and leave-one-out validation to evaluate heterogeneity and potential pleiotropy.

Cutaneous T-cell attracting chemokine (CTACK)/CCL27 (OR: 0.998 and 95% CI: 0.996-0.999) and interleukin-2 receptor α subunit (IL-2RA) (OR: 0.997 and 95% CI: 0.995-0.999) were inversely associated with the risk of joint pain, while interleukin-18 (IL-18) (OR: 1.0007 and 95% CI: 1.0001-1.0012) demonstrated a positive causal relationship. Sensitivity analyses supported the robustness of the main findings (Cochran's Q p = 0.413), though evidence of horizontal pleiotropy was detected (MR-Egger intercept p < 0.05).

This study identifies IL-18, CTACK, and IL-2RA as potential causal mediators of joint pain, providing genetic evidence that informs future precision approaches to analgesia. Future research should validate these findings across diverse populations and elucidate the molecular mechanisms underlying them to advance targeted therapies.