Tang Renzhe, You Xiaoqing, Yuan Botao, Ling Ziqiang, Li Yu
Department of Oncology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China.
School of Basic Medicine, Heilongjiang University of Chinese Medicine, Harbin, China.
Medicine (Baltimore). 2025 Sep 5;104(36):e44160. doi: 10.1097/MD.0000000000044160.
Numerous observational studies have suggested links between sex hormones and various autoimmune diseases (ADs). However, the causality of these associations remains uncertain. This study employs Mendelian randomization (MR) analysis to investigate the causal relationship between sex hormones and ADs risk. We conducted bidirectional MR using publicly available genome-wide association study summary statistics to explore the association between 4 sex hormones (total testosterone, bioavailable testosterone, estradiol, dehydroepiandrosterone sulfate), and sex-hormone-binding globulin with the risk of 14 common ADs. Causality was evaluated using the inverse variance weighted, MR Egger, weighted median, and Wald ratio methods. Sensitivity analyses included Cochran Q test, the MR Egger intercept test, and the leave-one-out approach. Higher genetically predicted levels of total testosterone were associated with a decreased risk of ankylosing spondylitis, type 1 diabetes, and primary biliary cholangitis. Higher levels of bioavailable testosterone were associated with a decreased risk of primary biliary cirrhosis and Sicca syndrome. Higher levels of estradiol were associated with increased risks of celiac disease. Higher levels of dehydroepiandrosterone sulfate were associated with increased risks of vitiligo. Higher levels of sex-hormone-binding globulin were associated with increased risks of rheumatoid arthritis and multiple sclerosis, but were associated with a decreased risk of type 1 diabetes. In the reverse MR analyses, 9 ADs showed causal relationships with sex hormones. The consistency of results across various methods and their validation through further sensitivity analyses confirm the robustness of the findings. This study demonstrates a causal association between sex hormones and the risk of a variety of ADs. These findings offer significant insights into the pathogenesis of ADs and suggest new avenues for future research and therapeutic strategies. Specifically, they highlight the potential of modulating sex hormone levels in the prevention and treatment of these disorders.
大量观察性研究表明性激素与多种自身免疫性疾病（ADs）之间存在关联。然而，这些关联的因果关系仍不确定。本研究采用孟德尔随机化（MR）分析来探究性激素与ADs风险之间的因果关系。我们利用公开可用的全基因组关联研究汇总统计数据进行双向MR分析，以探讨4种性激素（总睾酮、生物可利用睾酮、雌二醇、硫酸脱氢表雄酮）以及性激素结合球蛋白与14种常见ADs风险之间的关联。使用逆方差加权法、MR-Egger法、加权中位数法和Wald比率法评估因果关系。敏感性分析包括Cochran Q检验、MR-Egger截距检验和留一法。遗传预测的总睾酮水平较高与强直性脊柱炎、1型糖尿病和原发性胆汁性胆管炎风险降低相关。生物可利用睾酮水平较高与原发性胆汁性肝硬化和干燥综合征风险降低相关。雌二醇水平较高与乳糜泻风险增加相关。硫酸脱氢表雄酮水平较高与白癜风风险增加相关。性激素结合球蛋白水平较高与类风湿关节炎和多发性硬化症风险增加相关，但与1型糖尿病风险降低相关。在反向MR分析中，9种ADs显示出与性激素的因果关系。各种方法结果的一致性以及通过进一步敏感性分析的验证证实了研究结果的稳健性。本研究证明了性激素与多种ADs风险之间存在因果关联。这些发现为ADs的发病机制提供了重要见解，并为未来研究和治疗策略指明了新途径。具体而言，它们突出了调节性激素水平在预防和治疗这些疾病中的潜力。
