Abstract Details

Title Human Genetic Prioritization of Coagulation Cascade Proteins as Targets for Preventing Ischemic Stroke

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 13-019

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.

Authors/Disclosures
Iyas Daghlas, MD (UCSF) PRESENTER	Dr. Daghlas has nothing to disclose.
Ville Karhunen	Dr. Karhunen has nothing to disclose.
Anthony S. Kim, MD (UCSF Department of Neurology)	Dr. Kim has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for New England Journal of Medicine: Journal Watch. Dr. Kim has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Quintairos, Prieto, Wood & Boyer, PA. The institution of Dr. Kim has received research support from NIH/NCATS. The institution of Dr. Kim has received research support from NIH/NINDS. The institution of Dr. Kim has received research support from NIH/NIHMD. The institution of Dr. Kim has received research support from Patient-Centered Outcome Research Institute. The institution of Dr. Kim has received research support from American Heart Association. Dr. Kim has received personal compensation in the range of $500-$4,999 for serving as a Speaker with American Neurological Association.
Dipender P. Gill, MBBS, PhD	Dr. Gill has received personal compensation for serving as an employee of Sequoia Genetics Ltd. Dr. Gill has stock in Apollo Therapeutics. The institution of Dr. Gill has received research support from Medical Research Council.

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