Human Genetic Prioritization of Coagulation Cascade Proteins as Targets for Preventing Ischemic Stroke
Iyas Daghlas1, Ville Karhunen2, Anthony Kim1, Dipender Gill3
1Neurology, UCSF, 2University of Oulu, 3Imperial College London
Objective:
To identify coagulation cascade proteins that causally influence ischemic stroke risk.
Background:
While interindividual variations in coagulation protein concentration and function are risk factors for venous thromboembolism (VTE), their associations with arterial ischemic stroke are not well established. To address this knowledge gap, we integrated large-scale proteogenomic datasets to identify genetic proxies for lifelong, randomized perturbation of coagulation cascade proteins.
Design/Methods:
We performed Mendelian randomization (MR) and Bayesian colocalization analyses to test associations of these genetic proxies with risk of overall ischemic stroke (62,100 cases and 1,234,808 controls) and ischemic stroke subtypes (small vessel, large artery atherosclerotic, and cardioembolic stroke). We further contextualized associations with VTE and investigated secondary efficacy and bleeding outcomes.
Results:
This approach identified genetic proxies for 30 coagulation factors, with cross-trait associations revealing both known and novel interrelationships between coagulation cascade proteins. MR and colocalization analyses supported causal associations of genetically proxied levels of five proteins (factor XI, high-molecular-weight kininogen, prothrombin, protein C receptor [PROCR], y’ fibrinogen) with risk of ischemic stroke. These proteins all associated with the cardioembolic stroke subtype, with two proteins (y’ fibrinogen and prothrombin) further associating with the large artery atherosclerotic stroke subtype; there were no significant associations with risk of small vessel stroke. By contrast, genetic proxies for other coagulation factors (including factor V, factor VII, and protein S) showed selective associations with VTE risk.
Conclusions:
These findings implicate specific components of the coagulation cascade in ischemic stroke pathogenesis, while identifying proteins with specific roles in VTE. The therapeutic and clinical relevance of these findings warrants further investigation.
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