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American Journal of Epidemiology Advance Access published online on October 3, 2006
American Journal of Epidemiology, doi:10.1093/aje/kwj302
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.
Received June 16, 2005
Accepted April 12, 2006

HUMAN GENOME EPIDEMIOLOGY (HuGE) REVIEW

Endothelial Nitric Oxide Synthase Gene Polymorphisms and Cardiovascular Disease: A HuGE Review

Juan P. Casas 1, Gianpiero L. Cavalleri 2, Leonelo E. Bautista 3, Liam Smeeth 4, Steve Humphries 5, and Aroon D. Hingorani 6 *

1 Centre for Clinical Pharmacology, Department of Medicine, British Heart Foundation Laboratories at University College London, London, United Kingdom; Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
2 The Institute for Genome Science and Policy, Duke University, Durham, NC
3 Population Health Sciences, University of Wisconsin Medical School, Madison, WI
4 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
5 Centre for Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories at University College London, London, United Kingdom
6 Centre for Clinical Pharmacology, Department of Medicine, British Heart Foundation Laboratories at University College London, London, United Kingdom

* To whom correspondence should be addressed.
Aroon D. Hingorani, E-mail: a.hingorani{at}ucl.ac.uk


  Abstract

This review examines the association of a subset of endothelial nitric oxide synthase gene (NOS3) polymorphisms (Glu298Asp, intron 4, and -786T>C) with cardiovascular disease. The Glu298Asp polymorphism within exon 7 is the only common nonsynonymous variant. The variants have been associated with low plasma nitric oxide concentrations and reduced vascular reactivity; difficulties in measuring those phenotypes means that their functional role remains unclear. A large meta-analysis of NOS3 polymorphisms in coronary heart disease revealed per-allele odds ratios of 1.17 (95% confidence interval: 1.07, 1.28) for Glu298Asp, 1.17 (95% confidence interval: 1.07, 1.28) for -786T>C, and 1.12 (95% confidence interval: 1.01, 1.24) for intron 4. However, there was evidence that small studies with more striking results could affect the associations of the Glu298Asp and -786T>C polymorphisms with coronary heart disease. Associations of NOS3 polymorphisms with hypertension, preeclampsia, stroke, and diabetes remain uncertain. To date, no reliable gene-gene or gene-environmental interactions have been described. Use of these variants in predictive testing is unlikely to be useful, although the population attributable fraction could be substantial if the modest associations are causal. The need for large-scale genetic association studies using tagging polymorphisms is warranted to confirm or refute a role of the NOS3 gene in coronary heart disease.

Keywords: cardiovascular diseases; epidemiology; genotype; meta-analysis; nitric oxide synthase type III; NOS3; polymorphism, genetic; pre-eclampsia.
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