Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study
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Francesco Zito1, Gordon D O Lowe, Ann Rumley
1Centre for Cardiovascular Genetics, Royal Free and University College London Medical School, London WC1E 6JJ, UK.
Insights
The TT genotype of the Factor XII (FXII) 46C>T polymorphism increases coronary heart disease (CHD) risk in men with high cholesterol. Pravastatin treatment may enhance this risk, possibly due to reduced fibrinolysis.
Area of Science:
- Genetics and Cardiovascular Disease Research
- Molecular Biology and Thrombosis
- Clinical Trial Analysis
Background:
- The West of Scotland Coronary Prevention Study (WOSCOPS) established pravastatin's efficacy in reducing coronary heart disease (CHD) events.
- Factor XII (FXII) protein influences coagulation and fibrinolysis; elevated FXIIa levels correlate with increased CHD risk.
- Plasma FXIIa levels are significantly influenced by the FXII gene's 46C>T polymorphism.
Purpose of the Study:
- To investigate the association between the FXII 46C>T polymorphism and coronary heart disease (CHD) risk.
- To evaluate the impact of this polymorphism on pravastatin treatment efficacy in high-cholesterol men within the WOSCOPS trial.
Main Methods:
- Genotyping of 441 CHD cases and 990 controls from the WOSCOPS study for the FXII 46C>T polymorphism.
- Statistical analysis, including logistic regression, adjusted for cardiovascular risk factors.
- Measurement of plasma FXIIa levels in relation to genotypes.
Main Results:
- The TT genotype frequency was higher in CHD cases (11.8%) than controls (8.3%), indicating an independent CHD risk (OR 1.48).
- This increased risk associated with the TT genotype was significant only in the pravastatin group (OR 1.95), not the placebo group (OR 1.20).
- Men with CC or CT genotypes benefited significantly from pravastatin, while TT genotype individuals did not show significant benefit compared to placebo.
Conclusions:
- The FXII 46C>T polymorphism's TT genotype is linked to elevated CHD risk in high-cholesterol men.
- Reduced plasma FXIIa levels in TT genotype individuals may impair fibrinolysis, contributing to higher CHD risk.
- Pravastatin treatment might exacerbate this risk in TT genotype individuals, suggesting genotype-specific treatment responses.
Aim:
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.
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