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HEMATOLOGY / BASIC RESEARCH
Bidirectional two-sample Mendelian randomization analysis identifies protein C rather than protein S or antithrombin-III as associated with deep venous thrombosis
1
Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai, China
2
Department of Obstetrics and Gynecology, Shanghai Pudong New area People’s Hospital, Shanghai, China
3
Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
These authors had equal contribution to this work
Submission date: 2024-02-14
Final revision date: 2024-05-01
Acceptance date: 2024-05-01
Online publication date: 2024-06-07
Publication date: 2025-02-28
Corresponding author
Ping Zheng
Department of Neurosurgery, Shanghai Pudong, New area People’s Hospital, 490 South Chuanhuan Road, Shanghai, China
Department of Neurosurgery, Shanghai Pudong, New area People’s Hospital, 490 South Chuanhuan Road, Shanghai, China
Arch Med Sci 2025;21(1):215-223
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Observational studies have indicated significant contributions of protein C and protein S to thrombotic diseases, yet the “anticoagulation paradox” in deep venous thrombosis (DVT) remains unresolved. Therefore, we conducted an investigation to discern the causal effects of protein C, protein S and antithrombin-III on DVT risk.
Material and methods:
We employed a two-sample (one to evaluate the gene-exposure relationship and the other to evaluate the gene-outcome relationship) bidirectional Mendelian randomization (MR) framework to assess the causal associations between protein C, protein S, antithrombin-III and DVT.
Results:
Genetic associations with DVT were extracted from a comprehensive genome-wide association study involving 484,598 individuals. In the multivariable MR analysis, the odds ratios for DVT per standard deviation (SD) increase were 1.005 (95% CI: 1.002–1.008; p < 0.001) for protein C, 0.997 (95% CI: 0.992–1.001; p = 0.146) for protein S, and 1.001 (95% CI: 0.998–1.005; p = 0.456) for antithrombin-III. A two-step MR mediation analysis revealed that the association between protein C and DVT was partially mediated by body mass index, with a mediated proportion of 11.4% (95% confidence interval, 2.3% to 79.2%).
Conclusions:
These findings provide insights into the genetic relationship between relative protein C rather than protein S or antithrombin-III levels and DVT, offering potential utility in identifying at-risk patients for DVT development.
Observational studies have indicated significant contributions of protein C and protein S to thrombotic diseases, yet the “anticoagulation paradox” in deep venous thrombosis (DVT) remains unresolved. Therefore, we conducted an investigation to discern the causal effects of protein C, protein S and antithrombin-III on DVT risk.
Material and methods:
We employed a two-sample (one to evaluate the gene-exposure relationship and the other to evaluate the gene-outcome relationship) bidirectional Mendelian randomization (MR) framework to assess the causal associations between protein C, protein S, antithrombin-III and DVT.
Results:
Genetic associations with DVT were extracted from a comprehensive genome-wide association study involving 484,598 individuals. In the multivariable MR analysis, the odds ratios for DVT per standard deviation (SD) increase were 1.005 (95% CI: 1.002–1.008; p < 0.001) for protein C, 0.997 (95% CI: 0.992–1.001; p = 0.146) for protein S, and 1.001 (95% CI: 0.998–1.005; p = 0.456) for antithrombin-III. A two-step MR mediation analysis revealed that the association between protein C and DVT was partially mediated by body mass index, with a mediated proportion of 11.4% (95% confidence interval, 2.3% to 79.2%).
Conclusions:
These findings provide insights into the genetic relationship between relative protein C rather than protein S or antithrombin-III levels and DVT, offering potential utility in identifying at-risk patients for DVT development.
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