Background Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. Methods We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. Findings In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. Interpretation These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males. All data relevant to perform the multivariable Mendelian randomisation analyses are included as online supplemental information (G-X and G-Y in online supplemental table S2). Individual participant data may be obtained from a third party and are not publicly available. Please consult the data access policy of the UK Biobank at .

中文翻译：

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睾酮和性激素结合球蛋白对男性和女性肺功能的影响：多变量孟德尔随机研究

背景观察性研究表明，总睾酮（TT）和性激素结合球蛋白（SHBG）可能对肺功能有有益影响，但由于混杂和反向因果关系，这些发现可能是虚假的。我们通过使用多变量孟德尔随机化 (MVMR) 来研究 TT 和 SHBG 对肺功能的独立因果影响来解决这些局限性。方法 我们首先通过在英国大型生物库中分别对男性和女性进行 TT 和 SHBG 的全基因组关联分析来鉴定遗传工具。然后，我们使用单样本 MVMR 评估了 TT 和 SHBG 对 1 秒用力呼气量 (FEV1)、用力肺活量 (FVC) 和 FEV1/FVC 的独立影响。我们使用几种解释多效性的方法来解决可能导致 MVMR 偏差的问题。我们根据肥胖、体力活动和绝经状态进行了亚组 MVMR 分析，并评估了 TT 和 SHBG 与肺功能下降之间的关联。最后，我们将 MVMR 结果与英国生物银行的观察分析结果进行了比较。结果 在 MVMR 分析中，存在多效性的证据，但在解释它时结果是一致的。我们发现 TT 对男性和女性的 FVC 和 FEV1 都有很强的有益作用，但 SHBG 仅对男性的 FEV1 和 FEV1/FVC 有中等的有害作用。亚组分析表明，TT 对肥胖和老年男性的影响更大。观察分析与之前的研究一致，对于 TT 而言与 MRMV 一致，但对于 SHBG 则不然。解释 这些发现表明，睾酮可改善男性和女性的肺功能，而性激素结合球蛋白 (SHBG) 对男性具有相反的独立作用。与执行多变量孟德尔随机化分析相关的所有数据均作为在线补充信息包含在内（在线补充表 S2 中的 GX 和 GY）。个人参与者的数据可以从第三方获得，并且不公开。请查阅英国生物银行的数据访问政策：。