(Circulation. 1999;100:1515-1520.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
A Common Variant of the Endothelial Nitric Oxide Synthase (Glu298
Asp) Is a Major Risk Factor for Coronary Artery Disease in the UK
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-545.)
From the Clinical Pharmacology Unit, University of Cambridge Clinical School, Box 110, Addenbrooke's Hospital, Cambridge, UK.
Correspondence to Professor M.J. Brown, Clinical Pharmacology Unit, Level 6, Centre for Clinical Investigation (ACCI), Addenbrooke's Hospital, Box 110, Cambridge CB2 2QQ, UK. E-mail mjb14{at}medschl.cam.ac.uk
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 GluAsp amino
acid substitution at residue 298 of eNOS. We investigated the
relationship between this Glu298Asp 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 GT) which encodes a Glu298Asp
amino acid substitution in eNOS is a risk factor for angiographic CAD
and recent MI in this population.
Key Words: coronary disease • myocardial infarction • nitric oxide • genetics
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