Abstract
BACKGROUND: Males have a three times higher risk of a diagnosis of bladder cancer (Bca) than females. Sex hormone-binding globulin (SHBG) may be associated with Bca risk. However, the sex-specific role of SHBG in Bca remains unclear. In this study, we aimed to determine the role of SHBG in Bca. METHODS: A sex-specific univariable Mendelian randomization (MR) analysis involving 369,426 men and 395,375 women was conducted to assess the causal relationship between SHBG and testosterone and Bca risk. Sensitivity analyses and multivariable MR were conducted to confirm the robustness of our results. Linkage disequilibrium score regression assessed the genetic correlation between these diseases influenced by heredity. RESULTS: Univariable MR results showed that one-SD elevated SHBG was related to a low risk of Bca in males (OR: 0.60, 95% CI: 0.39-0.93; p = 0.022) but had no benefit in females. Genetically predicted BT was positively associated with Bca risk in males (OR: 1.59; 95% CI: 1.06-2.40; p = 0.027). In multivariable MR, higher SHBG levels were not related to male Bca risk after controlling for BT. CONCLUSIONS: Our findings do not provide evidence to support a causal relationship between SHBG and Bca risk in males although an association was observed in the univariable analysis. Further research is needed to identify the underlying pathways.