Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation
Abstract Background 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 rema...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-10-01
|
| Series: | Thrombosis Journal |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12959-023-00553-9 |
| _version_ | 1797557078554836992 |
|---|---|
| author | Shuping Wang Yongxiang Wang Ming Bai Yu Peng Dan Zhou Peng Lei Binpeng Zhou Piyi Zhang Zheng Zhang |
| author_facet | Shuping Wang Yongxiang Wang Ming Bai Yu Peng Dan Zhou Peng Lei Binpeng Zhou Piyi Zhang Zheng Zhang |
| author_sort | Shuping Wang |
| collection | DOAJ |
| description | Abstract Background 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). Methods 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. Results 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. Conclusion 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. |
| first_indexed | 2024-03-10T17:12:06Z |
| format | Article |
| id | doaj.art-73ac1aeb4d434138a534f9b42af62d53 |
| institution | Directory Open Access Journal |
| issn | 1477-9560 |
| language | English |
| last_indexed | 2024-03-10T17:12:06Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Thrombosis Journal |
| spelling | doaj.art-73ac1aeb4d434138a534f9b42af62d532023-11-20T10:36:47ZengBMCThrombosis Journal1477-95602023-10-0121111310.1186/s12959-023-00553-9Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisationShuping Wang0Yongxiang Wang1Ming Bai2Yu Peng3Dan Zhou4Peng Lei5Binpeng Zhou6Piyi Zhang7Zheng Zhang8The First Clinical Medical School, Lanzhou UniversityHeart Center, The First Hospital of Lanzhou UniversityThe First Clinical Medical School, Lanzhou UniversityHeart Center, The First Hospital of Lanzhou UniversityThe First Clinical Medical School, Lanzhou UniversityThe First Clinical Medical School, Lanzhou UniversityDepartment of Emergency, The First Hospital of Lanzhou UniversityThe First Clinical Medical School, Lanzhou UniversityThe First Clinical Medical School, Lanzhou UniversityAbstract Background 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). Methods 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. Results 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. Conclusion 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.https://doi.org/10.1186/s12959-023-00553-9Sex hormone-binding globulinTestosteroneVenous thromboembolismDeep vein thrombosisPulmonary embolismMendelian randomisation |
| spellingShingle | Shuping Wang Yongxiang Wang Ming Bai Yu Peng Dan Zhou Peng Lei Binpeng Zhou Piyi Zhang Zheng Zhang Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation Thrombosis Journal Sex hormone-binding globulin Testosterone Venous thromboembolism Deep vein thrombosis Pulmonary embolism Mendelian randomisation |
| title | Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation |
| title_full | Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation |
| title_fullStr | Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation |
| title_full_unstemmed | Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation |
| title_short | Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation |
| title_sort | causal inference of sex hormone binding globulin on venous thromboembolism evidence from mendelian randomisation |
| topic | Sex hormone-binding globulin Testosterone Venous thromboembolism Deep vein thrombosis Pulmonary embolism Mendelian randomisation |
| url | https://doi.org/10.1186/s12959-023-00553-9 |
| work_keys_str_mv | AT shupingwang causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT yongxiangwang causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT mingbai causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT yupeng causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT danzhou causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT penglei causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT binpengzhou causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT piyizhang causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation AT zhengzhang causalinferenceofsexhormonebindingglobulinonvenousthromboembolismevidencefrommendelianrandomisation |