Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation

Thrombosis Journal

Research

Binpeng Zhou¹  Yu Peng²  Yongxiang Wang²  Piyi Zhang³  Dan Zhou³  Shuping Wang⁴  Peng Lei⁴  Ming Bai⁵  Zheng Zhang⁵ 

[1] Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Gansu Provincial Clinical Research Center for Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Gansu Key Laboratory of Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;The First Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China;Gansu Key Laboratory of Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;The First Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China;Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Gansu Provincial Clinical Research Center for Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;The First Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China;Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Gansu Provincial Clinical Research Center for Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;Gansu Key Laboratory of Cardiovascular Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China;

关键词: Sex hormone-binding globulin;    Testosterone;    Venous thromboembolism;    Deep vein thrombosis;    Pulmonary embolism;    Mendelian randomisation;    Instrumental variables;   

DOI  :  10.1186/s12959-023-00553-9

 received in 2023-08-05, accepted in 2023-10-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPrevious 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).MethodsWe 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.ResultsOur 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.ConclusionOur 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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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