Unraveling the causal nexus of cathepsins and rheumatoid arthritis: Insights from a two-sample Mendelian randomization framework.

Rheumatoid arthritis (RA) is an autoimmune disease attacking joints throughout the body. Cathepsins (CTSs) are essential intracellular proteases participating in immune regulation, bone remodeling, and cartilage degradation. Though the observational and experimental studies have linked the biological functions of CTSs to the pathogenesis of RA, the cause-and-effect relationship between CTSs and RA remains unclear. Mendelian randomization (MR) recruited the single nucleotide polymorphism (SNP) associations of CTSs, including CTSB, CTSE, CTSF, CTSG, CTSH, CTSO, CTSS, CTSL2, and CTSZ, from 3301 individuals in the genome-wide association studies datasets to link the causal relationships between CTSs and RA (8255 RA cases and 409,001 controls). Inverse-variance weighted (IVW), MR-Egger, and weighted median (WM) methods were employed to reinforce the casual relationship. Robust sensitivity analyses, including the Cochran Q test, MR-Egger intercept test, and leave-one-out method, were conducted to validate the reliability. A significant causal correlation between CTSS and RA was identified post Bonferroni correction indicated by IVW (odds ratio [OR]: 1.04, 95% confidence interval [CI]: 1.02-1.07, P = 5.15 × 10-4), MR-Egger test (OR: 1.06, 95% CI: 1.02-1.10, P = 4.71 × 10-3), and WM (OR: 1.04, 95% CI: 1.01-1.07, P = .018). The reliability and consistency of our findings were confirmed. Specifically, no statistical heterogeneity among SNPs was identified (IVW, Q = 35.001, P = .832; MR-Egger, Q = 33.860, P = .839), nor did the evidence for horizontal pleiotropy (MR-Egger intercept test, P = .291). No SNP exerted a substantial impact on the outcome (leave-one-out method). Moreover, the remaining 8 CTSs did not exhibit causal relationship with RA (IVW, MR-Egger test, and WM, P > .05). And, the MR Steiger test confirmed the correctness of directionality. Elevated CTSS levels increased RA risk, which suggests a great potential of CTSS to serve a promising biomarker in RA prediction and prognosis and shows light on developing a CTSS-based therapeutic strategy in RA treatment.