Causal association of cathepsins and endometriosis: A Mendelian randomization study

Endometriosis is a prevalent reproductive disorder that affects a significant number of women globally. Cathepsins, which are lysosomal cysteine proteases, contribute to several physiological and pathological processes, including the attachment and invasion of endometrial tissue. Nevertheless, the causal relationship between cathepsins and endometriosis remains undetermined. The aim of this study was to explore the potential relationship between cathepsins and endometriosis using genetic polymorphisms. We employed a 2-sample Mendelian randomization (MR) analysis (including inverse-variance weighted [IVW] method and reverse MR analysis) to investigate the causal association between 9 cathepsins and endometriosis. The IVW method provides efficient and robust causal estimates when genetic instruments are valid, making it the standard approach in MR analysis. And the reverse MR analysis ensures the robustness and directionality of causal inference. The univariable MR analysis results indicate that Cathepsin H increases the risk of overall endometriosis (IVW: OR [95%] = 1.037 [1.007 to 1.067], P = .013), endometriosis of ovary (IVW: OR [95%] = 1.022 [1.001 to 1.042], P = .046), endometriosis of pelvic peritoneum OR [95%] = 1.046 [1.002 to 1.089], P = .047), and deep endometriosis (IVW: OR [95%] = 1.050 [1.002 to 1.099], P = .048). The multivariable MR analysis retained stable after adjusting for other types of cathepsins. And reverse MR analyses suggest that overall endometriosis may lead to increased Cathepsin H levels (IVW: OR [95%] = 1.017 [1.003, 1.073], P = .041). The results of the sensitivity analyses were consistent with the main findings. Our MR analysis yields robust evidence supporting a causal relationship between Cathepsin H and the susceptibility to endometriosis, potentially inspiring directions in endometriosis diagnosis and treatment.