Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study.
OBJECTIVE
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 CHD. 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 CHD. 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 (0.40-0.79) 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.
Zito
Francesco
F
Centre for Cardiovascular Genetics, Royal Free and University College London Medical School, London WC1E 6JJ, UK.
Lowe
Gordon D O
GD
Rumley
Ann
A
McMahon
Alex D
AD
Humphries
Steve E
SE
D016022:Case-Control Studies; D015331:Cohort Studies; D016001:Confidence Intervals; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D005174:Factor XII / Q000032:analysis / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000175:diagnosis / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011336:Probability; D018570:Risk Assessment; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
D005819:Genetic Markers; D000960:Hypolipidemic Agents; D005174:Factor XII