A Common Variant of the Endothelial Nitric Oxide Synthase (Glu 298 →Asp) Is a Major Risk Factor for Coronary Artery Disease in the UK

Abstract

Background —Endothelium-derived nitric oxide (NO) is synthesised from l -arginine by endothelial nitric oxide synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because reduced NO synthesis has been implicated in the development of coronary atherosclerosis, which has a heritable component, we hypothesised that polymorphisms of NOS 3 might be associated with increased susceptibility to this disorder. Methods and Results —Single-strand conformation polymorphism analysis of NOS 3 identified a G→T polymorphism in exon 7 of the gene which encodes a Glu→Asp amino acid substitution at residue 298 of eNOS. We investigated the relationship between this Glu 298 →Asp variant and atherosclerotic coronary artery disease (CAD) using 2 independent case-controlled studies. In the first study (CHAOS), cases consisted of 298 unrelated patients with positive coronary angiograms and controls were 138 unrelated healthy individuals ascertained through a population health screen. In the second study (CHAOS II), the cases were 249 patients with recent myocardial infarction (MI), and a further 183 unrelated controls. There was an excess of homozygotes for the Asp 298 variant among patients with angiographic CAD, and among patients with recent MI when compared with their respective controls (35.9% versus 10.2%, P <0.0001 in CHAOS, and 18.1% versus 8.7%, P <0.02 in CHAOS II). In comparison to Glu 298 homozygotes, homozygosity for Asp 298 was associated with an odds ratio of 4.2 (95% CI, 2.3 to 7.9) for angiographic CAD and 2.5 (95% CI, 1.3 to 4.2) for MI. Conclusions —Homozygosity for a common NOS 3 polymorphism (894 G→T) which encodes a Glu 298 →Asp amino acid substitution in eNOS is a risk factor for angiographic CAD and recent MI in this population.