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Association of the factor XII 46C > T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study

Zito, F; Lowe, GDO; Rumley, A; McMahon, AD; Humphries, SE; WOSCOPS Study Grp,; (2002) Association of the factor XII 46C > T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study. ATHEROSCLEROSIS , 165 (1) 153 - 158.

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Abstract

To evaluate the contribution of the 46C > T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol. Background: WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHID. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHID. Plasma FXIIa levels are strongly determined by a 46C > T polymorphism in the FXII gene. Results: 441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P = 0.04). When compared with the CC+ CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01-2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09-3.47) and not in the placebo group (OR 1.20, 95%CI 0.72-2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46-0.81) and 0.56 (0.400.79) compared with 1.10 (0.64-1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (P < 0.001 by Kruskal-Wallis test). Conclusions: The TT genotype of the FXII 46C > T polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Type:Article
Title:Association of the factor XII 46C > T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study
Keywords:Factor XII, genotype, coronary heart disease, ACTIVATED FACTOR-XII, MIDDLE-AGED MEN, FIBRIN D-DIMER, MYOCARDIAL-INFARCTION, HAGEMAN-FACTOR, PLASMINOGEN-ACTIVATOR, HUMAN-PLASMA, FACTOR-VII, ARTERY-DISEASE, FACTOR-IX
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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