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An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men

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Author: Agema, W.R.P. · Maat, M.P.M. de · Zwinderman, A.H. · Kastelein, J.J.P. · Rabelink, T.J. · Boven, A.J. van · Feskens, E.J.M. · Boer, J.M.A. · Wall, E.E. van der · Jukema, J.W.
Institution: Gaubius Instituut TNO
Source:Clinical Science, 3, 107, 255-261
Identifier: 237983
doi: doi:10.1042/CS20030360
Keywords: Biology · Biomedical Research · Atherosclerosis · Coronary artery disease · Endothelial constitutive nitric oxide synthase (ecNOS) · Genetic polymorphism · Endothelial nitric oxide synthase · Angiography · Cigarette smoking · Clinical trial · Controlled clinical trial · Controlled study · Disease course · Disease severity · DNA polymorphism · Enzyme polymorphism · Genetic association · Genotype · Heart infarction · Heart muscle ischemia · Major clinical study · Randomized controlled trial · ST segment · Anticholesteremic Agents · Case-Control Studies · Coronary Angiography · Coronary Disease · Disease Progression · Genetic Predisposition to Disease · Humans · Male · Middle Aged · Myocardial Infarction · Myocardial Ischemia · Nitric Oxide Synthase · Nitric Oxide Synthase Type III · Polymorphism, Genetic · Pravastatin · Statistics, Nonparametric


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. Chemicals / CAS: endothelial nitric oxide synthase, 503473-02-7; pravastatin, 81131-74-0; Anticholesteremic Agents; Nitric Oxide Synthase Type III, EC; Nitric Oxide Synthase, EC; NOS3 protein, human, EC; Pravastatin, 81093-37-0