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Exploring the Causal Relationship Between Inflammatory Cytokines and Joint Pain: A Mendelian Randomization Study.
Zehui Yan1, Yujia Xi2, Changjiang Mu1
1Department of Orthopedic, Second Hospital of Shanxi Medical University, Taiyuan, China, sxmu.edu.cn.
Pain Research & Management
|February 25, 2026
Summary
This study used Mendelian randomization to investigate inflammatory cytokines and joint pain risk. Interleukin-18 (IL-18) showed a positive causal link, while CTACK and IL-2RA indicated inverse relationships, suggesting potential therapeutic targets.
Area of Science:
- Genetics and immunology
- Chronic disease research
- Pain mechanisms
Background:
- Joint pain is a significant global cause of chronic disability.
- The precise role of inflammatory cytokines in joint pain pathogenesis requires further elucidation.
- Limited treatment options exist for chronic joint pain.
Purpose of the Study:
- To explore the causal relationships between 41 inflammatory cytokines and joint pain risk using Mendelian randomization.
- To identify specific cytokines that may causally influence the development of joint pain.
- To provide genetic evidence for potential precision medicine approaches in pain management.
Main Methods:
- Mendelian randomization (MR) analysis was performed.
- Genome-wide association study (GWAS) summary statistics from European-ancestry populations were integrated.
- Instrumental variables were selected based on stringent statistical criteria (p < 1 × 10^-5).
- Inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods were employed for causal estimation.
- Sensitivity analyses, including Cochran's Q test and MR-Egger intercept analysis, were conducted to assess heterogeneity and pleiotropy.
Main Results:
- Interleukin-18 (IL-18) was found to have a positive causal association with joint pain risk.
- Cutaneous T-cell attracting chemokine (CTACK)/CCL27 and interleukin-2 receptor alpha subunit (IL-2RA) showed inverse causal associations with joint pain risk.
- Sensitivity analyses confirmed the robustness of the findings, although some evidence of horizontal pleiotropy was detected.
Conclusions:
- IL-18, CTACK, and IL-2RA are identified as potential causal mediators in joint pain.
- Genetic evidence supports these cytokines as targets for future precision analgesia strategies.
- Further research is recommended to validate these findings in diverse populations and explore underlying molecular mechanisms for targeted therapy development.
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