Ou Junyong, Bi Hai, Zhou Haobin, Zhang Zhanyi, Duan Peichen, Yin Haoming, Zhou Zezhen, Xie Zhixin, Tian Xiaojun, Ye Jianfei, Zhang Shudong
Department of Urology, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Open Med (Wars). 2025 Feb 28;20(1):20251163. doi: 10.1515/med-2025-1163. eCollection 2025.
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.
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.
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; = 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; = 0.027). In multivariable MR, higher SHBG levels were not related to male Bca risk after controlling for BT.
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.
男性被诊断为膀胱癌（Bca）的风险是女性的三倍。性激素结合球蛋白（SHBG）可能与Bca风险相关。然而，SHBG在Bca中的性别特异性作用仍不清楚。在本研究中，我们旨在确定SHBG在Bca中的作用。
进行了一项涉及369426名男性和395375名女性的性别特异性单变量孟德尔随机化（MR）分析，以评估SHBG、睾酮与Bca风险之间的因果关系。进行了敏感性分析和多变量MR以确认我们结果的稳健性。连锁不平衡评分回归评估了受遗传影响的这些疾病之间的遗传相关性。
单变量MR结果显示，SHBG升高一个标准差与男性Bca风险降低相关（比值比：0.60，95%置信区间：0.39 - 0.93；P = 0.022），但对女性无益处。基因预测的BT与男性Bca风险呈正相关（比值比：1.59；95%置信区间：1.06 - 2.40；P = 0.027）。在多变量MR中，在控制BT后，较高的SHBG水平与男性Bca风险无关。
我们的研究结果没有提供证据支持SHBG与男性Bca风险之间存在因果关系，尽管在单变量分析中观察到了关联。需要进一步研究以确定潜在途径。
