睾酮在男性和女性慢性肾脏病及肾功能中的作用：英国生物库中一项双向孟德尔随机研究。
The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank.
机构信息
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Patrick Manson Building, 7 Sassoon Road, Pokfulam, Hong Kong SAR, China.
School of Public Health and Health Policy, City University of New York, New York, NY, USA.
出版信息
BMC Med. 2020 Jun 4;18(1):122. doi: 10.1186/s12916-020-01594-x.
BACKGROUND
Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available.
METHODS
We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly (p value < 5 × 10) predicted testosterone in a sex-specific manner were applied to 179,916 white British men (6016 CKD cases) and 212,079 white British women (5958 CKD cases) to obtain sex-specific associations with CKD, albuminuria, and estimated glomerular filtration rate (eGFR). We also used multivariable MR to control for sex hormone binding globulin (SHBG). For validation, we similarly examined their role in hemoglobin and high-density lipoprotein cholesterol (HDL-c). We also assessed the role of kidney function in serum testosterone, by applying eGFR-related SNPs to testosterone in the UK Biobank.
RESULTS
Genetically predicted testosterone was associated with CKD in men (odds ratio (OR) for bioavailable testosterone 1.17 per standard deviation, 95% confidence interval (CI) 1.03 to 1.33) based on 125 SNPs but not in women (OR 1.02, 95% CI 0.92 to 1.14 for total testosterone) based on 254 SNPs. Multivariable MR allowing for SHBG showed consistent patterns. Genetically predicted bioavailable testosterone in men and women and genetically predicted total testosterone in women increased hemoglobin and lowered HDL-c, as seen in RCTs. Genetically predicted eGFR was not related to serum testosterone in men or in women.
CONCLUSIONS
Genetically predicted testosterone was associated with CKD and worse kidney function in men, whilst not affected by kidney function. Identifying drivers of testosterone and the underlying pathways could provide new insights into CKD prevention and treatment.
背景
慢性肾脏病（CKD）存在明显的性别差异，男性的进展速度快于女性。之前尚未考虑过生殖与长寿之间这种已确立的、具有性别特异性的进化生物学权衡是否会影响 CKD。目前尚无来自随机对照试验（RCT）的相关证据。
方法
我们使用双向孟德尔随机化研究，通过英国生物库获得无偏倚的估计值。应用与性别特异性相关的、预测睾丸酮作用较强的单核苷酸多态性（SNP；p 值<5×10），对 179916 名英国白人男性（6016 例 CKD 患者）和 212079 名英国白人女性（5958 例 CKD 患者）进行分析，以获得与 CKD、白蛋白尿和估算肾小球滤过率（eGFR）相关的性别特异性关联。我们还使用多变量 MR 来控制性激素结合球蛋白（SHBG）。为了验证，我们同样研究了它们在血红蛋白和高密度脂蛋白胆固醇（HDL-c）中的作用。我们还通过将与 eGFR 相关的 SNP 应用于英国生物库中的睾丸酮，评估了肾脏功能对血清睾丸酮的作用。
结果
基于 125 个 SNP，遗传预测的睾丸酮与男性 CKD 相关（生物可利用的睾丸酮每标准差的比值比（OR）为 1.17，95%置信区间（CI）为 1.03 至 1.33），但在女性中没有相关性（总睾丸酮的 OR 为 1.02，95%CI 为 0.92 至 1.14），基于 254 个 SNP。允许 SHBG 参与的多变量 MR 显示出一致的模式。男性和女性遗传预测的生物可利用睾丸酮和女性遗传预测的总睾丸酮增加了血红蛋白并降低了 HDL-c，这与 RCT 所见一致。遗传预测的 eGFR 与男性或女性的血清睾丸酮无关。
结论
遗传预测的睾丸酮与男性 CKD 和更差的肾功能相关，而与肾功能无关。确定睾丸酮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。
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