Wang Shuping, Wang Yongxiang, Bai Ming, Peng Yu, Zhou Dan, Lei Peng, Zhou Binpeng, Zhang Piyi, Zhang Zheng
The First Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China.
Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
Thromb J. 2023 Oct 25;21(1):109. doi: 10.1186/s12959-023-00553-9.
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.
既往队列研究表明，使用外源性性激素，如睾酮替代疗法和含雌激素的避孕药，可增加静脉血栓栓塞（VTE）风险。然而，内源性性激素水平与VTE之间的关系仍不明确。本研究的目的是探讨内源性性激素，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，即深静脉血栓形成（DVT）和肺栓塞（PE）中的因果作用。
我们使用性激素的全基因组关联研究作为暴露数据，芬兰VTE数据作为结局数据。采用逆方差加权、MR-Egger和加权中位数方法进行两样本孟德尔随机化（MR）分析。敏感性分析包括MR-Egger、MR-PRESSO、Cochrane Q检验、MR Steiger、留一法分析和漏斗图，并结合多变量MR分析以及使用来自全球生物银行荟萃分析倡议的更大VTE数据进行重复MR分析。使用连锁不平衡评分回归（LDSC）来确定遗传关联并估计样本重叠情况。
我们的研究结果通过遗传预测表明，血清SHBG水平每增加一个标准差（SD），VTE风险增加25%（OR：1.25，95%CI：1.01-1.55），PE风险增加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SHBG对男性和女性VTE均有遗传效应（OR：1.46，95%CI：1.20-1.78），对女性的效应为（OR：1.49，95%CI：1.17-1.91）。此外，血清TT水平每增加一个SD，VTE风险增加32%（OR：1.32，95%CI：1.08-1.62），DVT风险增加31%（OR：1.31，95%CI：1.01-1.69）；然而，LDSC和重复分析未发现TT与VTE或其亚型之间存在遗传相关性。未观察到BT与所有三个结局性状之间存在显著相关性。
我们的研究提供了证据表明，如遗传学所预测的，血清SHBG水平升高会增加VTE风险。然而，睾酮水平对VTE的因果效应需要进一步研究。
