Aru Na, Yang Congyu, Chen Yuntian, Liu Jiaming
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
Medicine (Baltimore). 2025 May 23;104(21):e42579. doi: 10.1097/MD.0000000000042579.
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.
子宫内膜异位症是一种常见的生殖系统疾病，全球有大量女性受其影响。组织蛋白酶是溶酶体半胱氨酸蛋白酶，参与多种生理和病理过程，包括子宫内膜组织的黏附和侵袭。然而，组织蛋白酶与子宫内膜异位症之间的因果关系仍未确定。本研究旨在利用基因多态性探讨组织蛋白酶与子宫内膜异位症之间的潜在关系。我们采用两样本孟德尔随机化（MR）分析（包括逆方差加权[IVW]法和反向MR分析）来研究9种组织蛋白酶与子宫内膜异位症之间的因果关联。当基因工具有效时，IVW法可提供高效且稳健的因果估计，这使其成为MR分析中的标准方法。而反向MR分析可确保因果推断的稳健性和方向性。单变量MR分析结果表明，组织蛋白酶H会增加总体子宫内膜异位症的风险（IVW：OR[95%]=1.037[1.007至1.067]，P=0.013）、卵巢子宫内膜异位症的风险（IVW：OR[95%]=1.022[1.001至1.042]，P=0.046）、盆腔腹膜子宫内膜异位症的风险（OR[95%]=1.046[1.002至1.089]，P=0.047）以及深部子宫内膜异位症的风险（IVW：OR[95%]=1.050[1.002至1.099]，P=0.048）。在对其他类型的组织蛋白酶进行校正后，多变量MR分析结果保持稳定。反向MR分析表明，总体子宫内膜异位症可能导致组织蛋白酶H水平升高（IVW：OR[95%]=1.017[1.003，1.073]，P=0.041）。敏感性分析结果与主要发现一致。我们的MR分析产生了有力证据，支持组织蛋白酶H与子宫内膜异位症易感性之间的因果关系，这可能为子宫内膜异位症的诊断和治疗提供方向。
