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 Glu²⁹⁸→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 Asp²⁹⁸ 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 Glu²⁹⁸ homozygotes, homozygosity for Asp²⁹⁸ 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 Glu²⁹⁸→Asp amino acid substitution in eNOS is a risk factor for angiographic CAD and recent MI in this population.