【摘要】 目的 流行病学调查探讨了自身免疫性甲状腺功能亢进症（autoimmune hyperthyroidism, AH）与患乳腺癌（breast cancer, BC）风险之间的关联，但受混杂因素的限制，因果关系存在争议，潜在的中介途径也不明确。本研究致力于调查AH与BC遗传易感性的关系，以及两者之间潜在的中介因素。方法 本研究采用双样本孟德尔随机化（mendelian randomization, MR）方法，揭示了AH与BC及其亚型（ER+性型、ER-性型、Luminal A型、Luminal B型、Luminal B型Her2阴性、HER2阳性型和三阴型）之间的因果关系。并采用两步法孟德尔随机化（two step MR, TSMR）法探究免疫调节因子的中介作用。采用逆方差加权法（Inverse variance weighting, IVW）作为主要的MR分析方法，通过Cochran Q检验评估异质性，结合MR-Egger截距项和MR-PRESSO方法检测多效性，确保研究结果的稳健可靠。结果 基因预测的AH与Luminal B型乳腺癌存在因果关系(OR=0.940, 95%CI:0.900～0.983,P=6.058×10^-3),而未发现AH与其他乳腺癌亚型存在因果关联。研究证实组织蛋白酶Z（CTSZ）是AH与Luminal B型乳腺癌关联的中介因子，其中介比率为11.494%（95%CI:2.124%～43.623%）)。结论 本研究表明，AH可增加CTSZ的表达，从而降低Luminal B型乳腺癌的遗传易感性，了解这一机制为乳腺癌预防策略和干预措施的发展提供了新的见解。更多还原

【Abstract】 Objective To explore the relationship between AH and genetic susceptibility of BC, as well as the potential mediating mechanisms, given that epidemiological investigations have explored the association between autoimmune hyperthyroidism（AH） and the risk of developing breast cancer（BC） while the causality is controversial and the potential mediating pathways remain unclear due to confounding factors. Methods Two-sample Mendelian randomization（MR） was employed to investigate the causal relationship between AH and BC, with molecularly stratified analyses encompassing all receptor-defined subtypes（ER+BC, ER-BC, luminal A-like, luminal B-like, luminal B/HER2-negative-like, HER2-enriched-like, and TNBC）. Additionally, the two-step Mendelian randomization（TSMR） method was used to investigate the mediating role of immune regulatory factors. Statistical inference primarily utilized inverse variance-weighted（IVW） estimators, complemented by pleiotropy-robust sensitivity validation protocols. Heterogeneity was evaluated using Cochran’s Q test. Pleiotropy was detected by combining the MR-Egger intercept term and the MR-PRESSO method to ensure the robustness and reliability of the research results. Results Genetically predicted AH was causally associated with luminal B-like BC(OR=0.940, 95%CI: 0.900-0.983, P=6.05×10^-3), whereas AH was not observed to be causally associated with other subtypes of overall BC. The cathepsin Z（CTSZ） was determined to be a mediator of the association between AH and luminal B-like BC, with a mediation ratio of 11.494%（95%CI: 2.124%-43.623%）. Conclusion This study suggests that AH increases the expression of CTSZ and thus reduces the genetic susceptibility to luminal B-like BC, and understanding this mechanism provides new insights for the development of BC prevention strategies and interventions.更多还原