School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
City University of New York, School of Public Health and Health Policy, New York, New York.
J Am Soc Nephrol. 2021 Mar;32(3):686-694. doi: 10.1681/ASN.2020050659. Epub 2020 Dec 14.
Kidney function declines faster in men. Testosterone levels may mediate the sex disparity. Correspondingly, levels of sex hormone binding globulin (SHBG), which modulates sex hormones, might also be relevant to the lower kidney function in men. The sex-specific role of SHBG is unclear.
A sex-specific, Mendelian randomization (MR) study provided unconfounded estimates of SHBG levels among the United Kingdom Biobank population. Univariable MR applied 357 single nucleotide polymorphisms (SNPs) in men and 359 SNPs in women. These published SNPs strongly (<5×10) predict SHBG level. They were profiled in 179,916 white British men (6016 patients with CKD) and 212,079 white British women (5958 patients with CKD), to obtain the effect of SHBG on CKD, albuminuria, and eGFR. Multivariable MR controlling for testosterone was used to assess the effect of SHBG on CKD and kidney function independent of testosterone in men.
Genetically predicted higher SHBG was associated with a lower risk of CKD in men (odds ratio [OR], 0.78 per SD; 95% confidence interval [95% CI], 0.65 to 0.93) but had no benefit in women. The effect in men remained in multivariable MR, allowing for testosterone (OR, 0.61; 95% CI, 0.45 to 0.82).
Genetically predicted higher SHBG was associated with a lower risk of CKD and better kidney function in men, but not in women, suggesting that SHBG may play a role in CKD specifically in men. Identifying drivers of SHBG and the underlying pathways could provide new insights into CKD prevention and treatment.
男性的肾功能下降速度更快。睾丸激素水平可能介导了这种性别差异。相应地，调节性激素的性激素结合球蛋白（SHBG）水平可能也与男性较低的肾功能有关。SHBG 的性别特异性作用尚不清楚。
一项基于性别的孟德尔随机化（MR）研究在英国生物库人群中提供了不受干扰的 SHBG 水平估计值。单变量 MR 应用了 357 个男性 SNP 和 359 个女性 SNP。这些已发表的 SNP 强烈（<5×10）预测了 SHBG 水平。它们在 179916 名白人英国男性（6016 名 CKD 患者）和 212079 名白人英国女性（5958 名 CKD 患者）中进行了分析，以获得 SHBG 对 CKD、白蛋白尿和 eGFR 的影响。多变量 MR 控制了睾丸激素，用于评估 SHBG 对 CKD 和男性睾丸激素独立的肾功能的影响。
遗传预测的 SHBG 水平升高与男性患 CKD 的风险降低相关（优势比[OR]，每 SD 降低 0.78；95%置信区间[95%CI]，0.65 至 0.93），但对女性没有益处。在允许考虑睾丸激素的多变量 MR 中，男性的这种影响仍然存在（OR，0.61；95%CI，0.45 至 0.82）。
遗传预测的 SHBG 水平升高与男性 CKD 风险降低和肾功能改善相关，但对女性没有影响，这表明 SHBG 可能在男性中特异性地在 CKD 中发挥作用。确定 SHBG 的驱动因素及其潜在途径可能为 CKD 的预防和治疗提供新的见解。
