Genetically proxied inhibition of coagulation factors and risk of cardiovascular disease: a mendelian randomization study
Author(s)
Type
Journal Article
Abstract
Background
We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases.
Methods and Results
Genetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large‐artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.
Conclusions
This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases.
Methods and Results
Genetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large‐artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.
Conclusions
This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
Date Issued
2021-04-20
Date Acceptance
2021-02-15
Citation
Journal of the American Heart Association, 2021, 10 (8), pp.1-20
ISSN
2047-9980
Publisher
Wiley
Start Page
1
End Page
20
Journal / Book Title
Journal of the American Heart Association
Volume
10
Issue
8
Copyright Statement
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000641743900024&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
cardiovascular disease
coagulation
Mendelian randomization analysis
stroke
venous thromboembolism
VENOUS THROMBOEMBOLISM
ORAL ANTICOAGULANTS
ATRIAL-FIBRILLATION
FIBRINOGEN
METAANALYSIS
RIVAROXABAN
PREVENTION
DABIGATRAN
THROMBOSIS
ASPIRIN
Publication Status
Published
Article Number
ARTN e019644
Date Publish Online
2021-04-09