title: An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men.
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.
authors.affiliation: Department of Cardiology, Leiden University Medical Center, The Netherlands.
authors.forename: Willem R P
authors.initials: WR
authors.lastname: Agema
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Ad J
authors.initials: AJ
authors.lastname: van Boven
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.forename: Ernst E
authors.initials: EE
authors.lastname: van der Wall
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics*; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use; D018709:Statistics, Nonparametric
chemical_list: D000924:Anticholesteremic Agents; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin