Background: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts. Objectives: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke. Patients/Methods: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa-). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years. Results: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β = - 34.2 ± 3.5 nm; P = 3.3 × 10-22; minor allele frequency [MAF] = 0.23) and African-Americans (β = - 31.1 ± 7.9 nm; P = 9.0 × 10-5; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa-) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa- was associated with the ABO SNP rs657152 minor allele (β = 16.3 nm; P = 4.3 × 10-9; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa-, and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa+), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β = - 0.02; standard error = 0.08; P = 0.81). Conclusions: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo.
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