Casas Juan P, Cavalleri Gianpiero L, Bautista Leonelo E, Smeeth Liam, Humphries Steve E, Hingorani Aroon D
Centre for Clinical Pharmacology, Department of Medicine, British Heart Foundation Laboratories at University College London, London, United Kingdom.
Am J Epidemiol. 2006 Nov 15;164(10):921-35. doi: 10.1093/aje/kwj302. Epub 2006 Oct 3.
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.
本综述探讨了内皮型一氧化氮合酶基因（NOS3）多态性的一个子集（Glu298Asp、内含子4和-786T>C）与心血管疾病的关联。外显子7内的Glu298Asp多态性是唯一常见的非同义变异。这些变异与血浆一氧化氮浓度降低和血管反应性降低有关；测量这些表型存在困难，这意味着它们的功能作用仍不清楚。一项关于冠心病中NOS3多态性的大型荟萃分析显示，Glu298Asp的每等位基因优势比为1.17（95%置信区间：1.07，1.28），-786T>C为1.17（95%置信区间：1.07，1.28），内含子4为1.12（95%置信区间：1.01，1.24）。然而，有证据表明，结果更为显著的小型研究可能会影响Glu298Asp和-786T>C多态性与冠心病的关联。NOS3多态性与高血压、先兆子痫、中风和糖尿病的关联仍不确定。迄今为止，尚未描述可靠的基因-基因或基因-环境相互作用。在预测性检测中使用这些变异不太可能有用，尽管如果适度的关联是因果关系，人群归因分数可能很大。有必要进行大规模的基因关联研究，使用标签多态性来证实或反驳NOS3基因在冠心病中的作用。
