Revealing the causal relationship between cathepsin and inflammatory disease of wrist through Mendelian randomization

Although observational studies have suggested associations between cathepsins and inflammatory wrist diseases, critical controversies persist regarding the causality, directionality, and disease-specific mechanisms of these relationships. Conventional clinical studies are unable to determine whether cathepsin-disease associations reflect true causality or spurious links driven by confounding factors or reverse causation. Moreover, systematic causal analyses focusing on protease-mediated mechanisms in wrist-specific inflammatory pathologies remain notably absent. To address these gaps, this study employs bidirectional 2-sample Mendelian randomization (MR) to investigate the causal effects of cathepsins on inflammatory wrist diseases and elucidate their disease-specific roles, thereby providing genetic evidence for targeted therapeutic strategies. We performed bidirectional 2-sample MR using public genome-wide association study summary statistics to assess causal relationships between 10 cathepsins and 4 inflammatory wrist diseases. Instrumental variables (single nucleotide polymorphisms) were selected at genome-wide significance (P < 5 × 10⁻⁶, and r² < 0.001) for exposure-outcome associations. Causality was evaluated via inverse-variance weighted, MR-Egger, and Weighted Median methods. Sensitivity analyses included Cochran Q, MR-Pleiotropy Residual Sum and Outlier, MR-Egger and leave-one-out validation. Univariate MR analysis demonstrated a causal association between genetically determined levels of cathepsin S and the development of carpal tunnel syndrome (odds ratio [OR], 0.954 [95% CI, 0.925-0.984]; P = .003), wrist synovitis (OR, 0.708 [95% CI, 0.529-0.949]; P = .021), and rheumatoid arthritis (RA; OR, 1.048 [95% CI, 1.005-1.092]; P = .029). Similarly, a causal link was established between cathepsin L and RA (OR, 0.948 [95% CI, 0.906-0.991]; P = .019), and between cathepsin F and De Quervain tenosynovitis (OR, 1.213 [95% CI, 1.003-1.466]; P = .046). A reverse MR analysis suggested a causal relationship between cathepsin O and wrist synovitis (OR, 1.047 [95% CI, 1.003-1.093]; P = .038). No causal associations were found for other cathepsins with the diseases studied. The reliability of these findings was confirmed through various robustness tests. Genetic evidence confirms cathepsin S protects against carpal tunnel syndrome and wrist synovitis but increases RA risk. Cathepsin F is positively associated with De Quervain tenosynovitis. Conversely, wrist synovitis elevates cathepsin O levels through reverse causation. These findings validate pathogenic mechanisms of wrist inflammatory disorders and suggest targeted inhibition of specific cathepsins as a promising therapeutic strategy.