Application of human genetics to prioritize coagulation cascade protein targets for ischemic stroke prevention
Author(s)
Daghlas, Iyas
Karhunen, Ville
Kim, Anthony S
Gill, Dipender
Type
Journal Article
Abstract
BACKGROUND:
While interindividual variations in concentration and function of coagulation cascade proteins are established risk factors for venous thromboembolism (VTE), their associations with arterial ischemic stroke are less well defined.
METHODS:
We identified and validated genetic proxies for lifelong, randomized perturbations of coagulation cascade proteins in genome-wide association studies of circulating protein levels (deCODE, n=35 559; UK Biobank, n=46 218) and of VTE risk (81 190 cases and 1 419 671 controls). Study participants were all of European ancestry. We performed 2-sample Mendelian randomization and colocalization analyses to test associations of these genetic proxies with risk of ischemic stroke (62 100 cases and 1 234 808 controls from the GIGASTROKE consortium) and ischemic stroke subtypes, and further contextualized associations with VTE and secondary efficacy and safety outcomes.
RESULTS:
We identified genetic proxies for 30 coagulation factors, with cross-trait associations recapitulating canonical coagulation biology. Mendelian randomization and colocalization analyses supported causal associations of genetically proxied levels of 5 proteins with risk of ischemic stroke, with all proteins associating with the cardioembolic stroke subtype: factor XI (odds ratio [OR] of cardioembolic stroke per 1-SD increase, 1.31 [95% CI, 1.19–1.44]; P=3.30×10−8), high-molecular-weight kininogen (OR, 1.19 [95% CI, 1.09–1.30]; P=7.79×10−5), prothrombin (OR, 1.83 [95% CI, 1.31–2.57]; P=4.20×10−4), soluble PROCR (protein C receptor; OR, 0.88 [95% CI, 0.82–0.95]; P=6.19×10−4), and γ′ fibrinogen (OR per doubling in VTE risk due to lower γ′ fibrinogen levels, 1.44 [95% CI, 1.25–1.66]; P=3.96×10−7). γ′ Fibrinogen and prothrombin also associated with large artery atherosclerotic stroke, and no proteins were associated with small vessel stroke risk. By contrast, genetic proxies for several coagulation factors (including proteins C and S and factors V and VII) showed selective associations with VTE.
CONCLUSIONS:
These data highlight specific coagulation cascade components implicated in ischemic stroke pathogenesis, while identifying proteins with distinct roles in VTE. These findings may inform development of novel anticoagulants and optimize their use in targeted populations with stroke.
While interindividual variations in concentration and function of coagulation cascade proteins are established risk factors for venous thromboembolism (VTE), their associations with arterial ischemic stroke are less well defined.
METHODS:
We identified and validated genetic proxies for lifelong, randomized perturbations of coagulation cascade proteins in genome-wide association studies of circulating protein levels (deCODE, n=35 559; UK Biobank, n=46 218) and of VTE risk (81 190 cases and 1 419 671 controls). Study participants were all of European ancestry. We performed 2-sample Mendelian randomization and colocalization analyses to test associations of these genetic proxies with risk of ischemic stroke (62 100 cases and 1 234 808 controls from the GIGASTROKE consortium) and ischemic stroke subtypes, and further contextualized associations with VTE and secondary efficacy and safety outcomes.
RESULTS:
We identified genetic proxies for 30 coagulation factors, with cross-trait associations recapitulating canonical coagulation biology. Mendelian randomization and colocalization analyses supported causal associations of genetically proxied levels of 5 proteins with risk of ischemic stroke, with all proteins associating with the cardioembolic stroke subtype: factor XI (odds ratio [OR] of cardioembolic stroke per 1-SD increase, 1.31 [95% CI, 1.19–1.44]; P=3.30×10−8), high-molecular-weight kininogen (OR, 1.19 [95% CI, 1.09–1.30]; P=7.79×10−5), prothrombin (OR, 1.83 [95% CI, 1.31–2.57]; P=4.20×10−4), soluble PROCR (protein C receptor; OR, 0.88 [95% CI, 0.82–0.95]; P=6.19×10−4), and γ′ fibrinogen (OR per doubling in VTE risk due to lower γ′ fibrinogen levels, 1.44 [95% CI, 1.25–1.66]; P=3.96×10−7). γ′ Fibrinogen and prothrombin also associated with large artery atherosclerotic stroke, and no proteins were associated with small vessel stroke risk. By contrast, genetic proxies for several coagulation factors (including proteins C and S and factors V and VII) showed selective associations with VTE.
CONCLUSIONS:
These data highlight specific coagulation cascade components implicated in ischemic stroke pathogenesis, while identifying proteins with distinct roles in VTE. These findings may inform development of novel anticoagulants and optimize their use in targeted populations with stroke.
Date Issued
2025-06-01
Date Acceptance
2025-03-12
Citation
Stroke, 2025, 56 (6), pp.1542-1553
ISSN
0039-2499
Publisher
Lippincott, Williams & Wilkins
Start Page
1542
End Page
1553
Journal / Book Title
Stroke
Volume
56
Issue
6
Copyright Statement
© 2025 The Authors.Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. 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 that the original work is properly cited.
License URL
Identifier
10.1161/STROKEAHA.124.049808
Publication Status
Published
Date Publish Online
2025-04-06