Application of Human Genetics to Prioritize Coagulation Cascade Protein Targets for Ischemic Stroke Prevention.

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.