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Published on: October 15, 2010
An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease
Willem R P Agema1, Moniek P M de Maat, Aeilko H Zwinderman
1Department of Cardiology, Leiden University Medical Center, The Netherlands.
Insights
Genetic variations in the ecNOS gene are linked to coronary artery disease (CAD) and myocardial infarction (MI). The E/D298 polymorphism is most associated with CAD, while the D allele relates to ischemia.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Endothelial nitric oxide synthase (ecNOS) plays a crucial role in vascular health.
- Genetic polymorphisms in the ecNOS gene may influence susceptibility to cardiovascular diseases.
- Coronary artery disease (CAD) and myocardial infarction (MI) are significant public health concerns.
Purpose of the Study:
- To investigate the association between three ecNOS gene polymorphisms (-786T/C, E/D298, 4a/b) and the risk, severity, and progression of CAD, MI, and ischemia.
- To evaluate the impact of these polymorphisms on atherosclerosis progression in patients treated with pravastatin or placebo.
Main Methods:
- Genotyping of 760 CAD patients and 691 controls for ecNOS polymorphisms (-786T/C, E/D298, 4a/b).
- Randomized controlled trial with pravastatin or placebo to assess atherosclerosis progression via sequential angiography.
- Assessment of ischemic burden using ST segment analysis from ambulatory ECGs.
Main Results:
- The E298 and 4a alleles were significantly associated with the presence of CAD.
- The E298 and -786T alleles were linked to a history of MI, particularly in smokers.
- D/D298 homozygotes experienced longer-lasting ischemia compared to other genotypes.
- No significant differences in atherosclerosis progression were observed, regardless of pravastatin treatment.
Conclusions:
- The E/D298 polymorphism is strongly associated with CAD but not its progression.
- The E allele is linked to increased risk of CAD and MI.
- The D allele is associated with a greater burden of ischemia.
- ecNOS gene polymorphisms are relevant genetic factors in cardiovascular disease development.
Abstract:
In the present study, we sought to evaluate the role of three polymorphisms in the ecNOS (endothelial constitutive nitric oxide synthase) gene in relation to the existence, severity and progression of CAD (coronary artery disease), MI (myocardial infarction) and the occurrence of ischaemia in a predominantly Caucasian population. Patients with CAD (n = 760) and age- and sex-matched population-based controls (n = 691) were genotyped for the -786T/C, E/D298 and 4a/b polymorphisms. Patients were randomized to pravastatin (40 mg) or placebo. Progression of atherosclerosis was evaluated by sequential angiography. Functionality was assessed by ST segment analysis of ambulant ECGs. The E298 (P = 0.003) and 4a (P = 0.001) alleles were associated with CAD. Furthermore, E298 (P = 0.009) and -786T (P = 0.022) alleles were associated with previous MI among patients, predominantly smokers. D/D298 homozygotes, but not -786T/C or 4a/4b mutants, had longer-lasting ischaemia than others (P < 0.05). We found no differences in progression of atherosclerosis, irrespective of pravastatin use. We conclude that the E/D298 polymorphism is most consistently associated with CAD, but not with progression of atherosclerosis. The E allele is associated with CAD and MI, whereas the D allele is associated with ischaemia.
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