Causal association of cathepsins and endometriosis: A Mendelian randomization study

Na Aru, Congyu Yang, Yahong Chen, Jiaming Liu
In: Research Square · 2023 · doi:10.21203/rs.3.rs-3756621/v1 · W4389934354
preprint OA: green CC0
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This Mendelian randomization study found that increased Cathepsin H is causally associated with a higher risk of overall endometriosis and specific subtypes.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This preprint used a two-sample Mendelian randomization framework to test whether genetically predicted levels of nine cathepsins (lysosomal cysteine proteases) causally influence risk of endometriosis subtypes, using European GWAS data from FinnGen for overall endometriosis, ovarian, pelvic peritoneal, and deep disease and INTERVAL data for cathepsin instruments. In univariable analyses, Cathepsin H was positively associated with overall endometriosis (IVW OR 1.037, p=0.013) and with specific subtypes, including ovarian, pelvic peritoneum, and deep endometriosis, while other cathepsins showed no significant associations. Multivariable MR reportedly retained the association after adjusting for other cathepsins, reverse MR suggested that overall endometriosis may increase Cathepsin H levels, and sensitivity checks were described as consistent with the main findings. The study is a preprint and uses genetic instruments from European populations, which may limit generalizability. This paper is centrally about endometriosis — it provides Mendelian randomization evidence that Cathepsin H has a causal relationship with susceptibility to overall and subtype-specific endometriosis.

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Abstract

Abstract Objective 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. Methods We employed a two-sample Mendelian randomization (MR) analysis to investigate the causal association between nine cathepsins and endometriosis. Results 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 = 0.013), endometriosis of ovary (IVW: OR [95%]: 1.022 [1.001 to 1.042], p = 0.046), endometriosis of pelvic peritoneum OR [95%]: 1.046 [1.002 to 1.089], p = 0.047), and deep endometriosis (IVW: OR [95%]: 1.050 [1.002 to 1.099], p = 0.048). 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 = 0.041). The results of the sensitivity analyses were consistent with the main findings. Conclusion 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.

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endometriosis

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