Abstract
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.