Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study

Abstract

The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts. To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways exvivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke. We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n=5411), both with and without inhibitory anti-factorXIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~50000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2years. The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β=-34.2±3.5nm; P=3.3×10(-22) ; minor allele frequency [MAF]=0.23) and African-Americans (β=-31.1±7.9nm; 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=16.3nm; P=4.3×10(-9) ; MAF=0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI1.01-1.17; P=0.03) for pTG, 1.06 (95% CI0.98-1.15; P=0.17) for pTG/FXIa(-) , and 1.11 (95% CI1.02-1.21; 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). 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 exvivo and invivo.