Objective  To explore the causal relationship between cathepsins and autoimmune thyroid diseases (AITDs) using Mendelian randomization (MR) study, and to provide genetic evidence for the association between cathepsins and the risk of AITDs.

Methods  The pooled datasets of nine cathepsins (B, E, F, G, H, L2, O, S and Z) and four AITDs were selected from a publicly available genome-wide association study (GWAS) website. The generalized summary data-based MR (GSMR), univariate bidirectional MR, and multivariate MR (MVMR) were used to analyze the causal relationship between them and the independent effects of specific risk factors. Plasma protein quantitative trait loci (pQTL) genetic instrumental variables were obtained from the Ferkingstad study to verify causality at the protein level. The inverse variance weighted method (IVW) was used as the primary analytical approach of univariate bidirectional MR Analysis, supplemented by MR-Egger, weighted median method, simple model, and weighted model methods. Horizontal pleiotropy and heterogeneity were evaluated, and sensitivity analysis was performed to ensure the robustness of the results.

Results  GSMR and forward MR analysis showed that cathepsin F (CTSF) significantly reduced the risk of Graves disease (GD). Reverse MR Analysis showed no reverse causality between the GD and CTSF. After adjusting for the effects of other cathepsins, MVMR analysis confirmed that the correlation between CTSF and GD was still significant. Furthermore, the causal effect between CTSF and GD was verified by cis-pQTL MR.

Conclusion  There is a causal relationship between CTSF and the reduced risk of GD, and CTSF is a potential protective factor against GD.

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