Exploring the causal relationship between interleukin levels and osteoarthritis: A two-sample Mendelian randomization analysis

• Published in: Medicine (Baltimore) Vol. 104; no. 23; p. e42675
• Main Authors: Wu, Zhoutong, Zhou, Honghai, Wu, Zhouhan, Hou, Zhaomeng
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 06.06.2025
• Subjects: Female; Genome-Wide Association Study; Humans; Interleukin-18 - blood; Interleukin-18 - genetics; Interleukin-6 - blood; Interleukin-6 - genetics; Interleukins - blood; Interleukins - genetics; Male; Mendelian Randomization Analysis; Observational Study; Osteoarthritis - blood; Osteoarthritis - genetics; Polymorphism, Single Nucleotide; Mendelian randomization; causation; Interleukin; osteoarthritis; inflammatory
• ISSN: 1536-5964; 0025-7974; 1536-5964
• DOI: 10.1097/MD.0000000000042675

Osteoarthritis (OA) is a degenerative joint disease. It is a common cause of pain and chronic disability in the elderly population which places a heavy burden on countless families. Evidence suggests a strong association between interleukins and the pathogenesis of OA. However, the causal relationship between interleukins and OA has not been well established. The resolution of this question will provide clinical guidance for the prevention and diagnosis of OA. Therefore, we investigated the causal relationship between interleukins and OA by Mendelian randomization (MR) analysis. The OA data were obtained from a genome-wide association study involving 826,690 subjects from 9 populations, with 177,517 having OA. Additionally, 16 interleukins were selected as instrumental variables from a genome-wide association study of 8293 Europeans. The main experimental approach was the inverse variance weighting method. To enhance result reliability, 3 additional analyses were included: MR-Egger, weighted median, and weighted mode. False discovery rate correction using the Benjamin-Hochberg method was applied. Sensitivity analyses were conducted to detect heterogeneity or horizontal pleiotropy, with confidence further bolstered by the leave one out test. Reverse MR analysis concluded the study. We identified a causal relationship between interleukin (IL)-6 and IL-18 with OA. IL-6 (95% CI: 3-348, P = .00219) showed causal effects using the weighted median method (Beta = 3.653) and the weighted mode method (Beta = 3.657). IL-18 (95% CI: 2-17, P = .00050) exhibited causal effects using the weighted median method (Beta = 1.681) and the weighted mode method (Beta = 1.817). In sensitivity analyses, we excluded heterogeneity and horizontal pleiotropy of results, and the leave one out test also provides further evidence that the experimental results have a high degree of confidence. This MR analysis presents a strong case for a causative link between IL-6 and IL-18 and OA. These findings are significant for the development of preventive and therapeutic strategies for OA. Further investigation into the mechanisms underlying the action of interleukins in OA is necessary.