Previous cohort studies have shown that exogenous sex hormone use, such as testosterone replacement therapy and oestrogen-containing contraceptives, can increase the risk of venous thromboembolism (VTE). However, the relationship between endogenous sex hormone levels and VTE remains unclear. The goal of the present study was to explore the causal roles of endogenous sex hormones, including hormone-binding globulin (SHBG), bioactive testosterone (BT), and total testosterone (TT), in VTE and its two subgroups, deep vein thrombosis (DVT) and pulmonary embolism (PE). We used a genome-wide association study of sex hormones as exposure data and Finnish VTE data as the outcome. Inverse variance weighting, MR-Egger, and weighted median were used for two-sample Mendelian randomisation (MR). Sensitivity analyses included MR-Egger, MR-PRESSO, Cochrane Q test, MR Steiger, leave-one-out analysis, and funnel plot, combined with multivariate MR and replicated MR analyses using larger VTE data from the global biobank meta-analysis initiative. Linkage disequilibrium score regression (LDSC) was used to determine genetic associations and estimate sample overlap. Our findings genetically predicted that an increase in serum SHBG levels by one standard deviation (SD) caused 25% higher odds for VTE (OR: 1.25, 95% CI: 1.01−1.55) and 58% higher odds for PE (OR: 1.58, 95% CI: 1.20−2.08). LDSC supported the genetic correlation between these two traits and replicated analyses confirm SHBG’s genetic effect on VTE in both sexes (OR: 1.46, 95% CI: 1.20−1.78) and in females (OR: 1.49, 95% CI: 1.17−1.91). In addition, an increase in serum TT levels by one SD caused 32% higher odds for VTE (OR: 1.32, 95% CI: 1.08−1.62) and 31% higher odds for DVT (OR: 1.31, 95% CI: 1.01−1.69); however, LDSC and replicated analyses did not find a genetic correlation between TT and VTE or its subtypes. No significant correlation was observed between BT and all three outcome traits. Our study provides evidence that elevated serum SHBG levels, as predicted by genetics, increase VTE risk. However, the causal effect of testosterone levels on VTE requires further investigation.

中文翻译：

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性激素结合球蛋白与静脉血栓栓塞的因果推论：来自孟德尔随机化的证据

先前的队列研究表明，外源性激素的使用，例如睾酮替代疗法和含雌激素的避孕药，会增加静脉血栓栓塞（VTE）的风险。然而，内源性激素水平与 VTE 之间的关系仍不清楚。本研究的目的是探讨内源性激素，包括激素结合球蛋白 (SHBG)、生物活性睾酮 (BT) 和总睾酮 (TT) 在 VTE 及其两个亚组深静脉血栓形成中的因果作用。 DVT）和肺栓塞（PE）。我们使用性激素的全基因组关联研究作为暴露数据，并使用芬兰 VTE 数据作为结果。逆方差加权、MR-Egger 和加权中位数用于两样本孟德尔随机化 (MR)。敏感性分析包括 MR-Egger、MR-PRESSO、Cochrane Q 检验、MR Steiger、留一分析和漏斗图，以及使用来自全球生物样本库荟萃分析计划的更大 VTE 数据的多变量 MR 和重复 MR 分析。连锁不平衡评分回归（LDSC）用于确定遗传关联并估计样本重叠。我们的研究结果从基因上预测，血清 SHBG 水平增加一个标准差 (SD) 会导致 VTE 的几率增加 25%（OR：1.25，95% CI：1.01−1.55），PE 的几率增加 58%（OR：1.58， 95% CI：1.20−2.08）。LDSC 支持这两个性状之间的遗传相关性，重复分析证实了 SHBG 对两性（OR：1.46，95% CI：1.20−1.78）和女性（OR：1.49，95% CI：1.17−1.91）VTE 的遗传影响。此外，血清 TT 水平增加 1 个 SD 会导致 VTE 发生率增加 32%（OR：1.32，95% CI：1.08−1.62），DVT 发生率增加 31%（OR：1.31，95% CI：1.01−1.01−1）。 1.69）；然而，LDSC 和重复分析并未发现 TT 和 VTE 或其亚型之间存在遗传相关性。BT 与所有三个结果特征之间没有观察到显着相关性。我们的研究提供的证据表明，正如遗传学预测的那样，血清 SHBG 水平升高会增加 VTE 风险。然而，睾酮水平对 VTE 的因果影响需要进一步研究。