Epidemiological and genetic associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men

Background-The relations of plasma activated factor XII (FXIIa) concentrati on and a common polymorphism (C46T) of the factor XII gene with hemostatic status and risk of coronary heart disease (CHD) were examined by prospectiv e surveillance. Methods and Results-Genotyping for the C46T variant was performed in 2624 m en 50 to 61 years of age who were free of CHD at baseline. The genotype dis tribution was as follows: CC, 56.7%; CT; 36.9%; and TT, 6.6%. Plasma FXIIa was measured by ELISA on 1745 samples collected 1 year after baseline; medi an levels were (ng/mL) CC, 2.0; CT, 1.4, and TT, 0.8 (P<0.0001). Respective values for plasma fibrinopeptide A (FPA, nmol/L) were 1.52, 1.35, and 1.15 (P<0.0001); for factor VII coagulant activity (FVIIc, % standard), 114.5, 116.2, and 109.3 (P=0.02). Group differences in FVIIc were unchanged by adj ustment for body mass index and serum triglycerides. Whereas CHD incidence did not differ significantly by genotype, rates (per 1000 person-years) by thirds of FXIIa distribution were for <1.5 ng/mL, 7.2; for 1.5 to 2.0 ng/mL , 7.2; and for >2.0 ng/mL, 13.6. Respective hazard ratios with the low thir d as reference group were 1.01 and 1.96 (P=0.007), which were essentially u nchanged after allowance for genotype, blood lipids, blood pressure, body m ass index, FVIIc, and FPA. Conclusions-The C46T polymorphism is a determinant of FXIIa, FPA, and possi bly FVIIc, suggesting that FXII influences the activity state of the coagul ation pathway and FPA cleavage from fibrinogen in vivo. plasma FXIIa is inc reased in middle-aged men at high risk of CHD.