Causal relationship between interleukin-6 levels and the risk of synovitis and tenosynovitis: A two-sample Mendelian randomization study

Synovitis and tenosynovitis are common musculoskeletal disorders with multifactorial etiologies involving mechanical loading and inflammatory responses. Previous studies have suggested that interleukin-6 (IL-6) may play a critical role in tendon injury and repair; however, definitive evidence regarding a causal relationship between IL-6 levels and the risk of tenosynovitis remains lacking. This study employed a two-sample Mendelian randomization (MR) approach to evaluate the potential causal association between circulating IL-6 levels and the risk of tenosynovitis. Genetic instruments for IL-6 were derived from the protein quantitative trait loci (pQTL) study by Sun et al, which utilized a mass spectrometry platform. Outcome data were obtained from the FinnGen consortium (phenotype code: R12_M13_TENDOSYNOVITISNAS). Single nucleotide polymorphisms (SNPs) significantly associated with IL-6 (P < 5 × 10-6) were selected as instrumental variables. Primary causal estimates were obtained using inverse variance weighting (IVW), MR-Egger regression, weighted median, and weighted mode methods. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, leave-one-out analysis, and funnel plot symmetry assessment. The IVW analysis indicated a negative association between IL-6 levels and tenosynovitis risk (β = -0.0236, P = .2106), though this did not reach statistical significance. Consistent directions of effect were observed across MR-Egger, weighted median, and weighted mode approaches. Sensitivity analysis and heterogeneity test (Q = 9.35, P = .808) indicated no significant horizontal pleiotropy, heterogeneity, or outlier SNPs, suggesting that the model results are robust. This study, based on MR, explores the potential association between IL-6 levels and the risk of tenosynovitis from a genetic perspective, showing a non-significant negative trend. Although no clear causal evidence was found, these observations provide preliminary clues for future mechanistic studies and the exploration of IL-6 as a potential intervention target.