Occupational and Environmental Medicine, Department of Public Health & Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Occupational and Environmental Medicine, Department of Public Health & Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Nitric Oxide. 2014 May 30;39:1-7. doi: 10.1016/j.niox.2014.03.164. Epub 2014 Apr 5.
Nitric oxide synthase (NOS) exists in three distinct isoforms, each encoded by a specific gene: neuronal NOS (NOS1 gene), inducible NOS (NOS2 gene) and endothelial NOS (NOS3 gene). Single nucleotide polymorphisms (SNPs) in NOS genes have been associated with cardiovascular pathology. We aimed to comprehensively investigate which NOS gene variants are most strongly associated with coronary heart disease (CHD) and hypertension, using a set of tagging SNPs with good coverage across the 3 genes.
CHD cases (n=560) and randomly selected population controls (n=2791) were genotyped at 58 SNPs in the NOS genes. Control individuals with systolic blood pressure ≥140, diastolic blood pressure ≥90 or on antihypertensive medication were defined as hypertensive. A structured stepwise logistic regression approach was used to select the SNPs most strongly associated with CHD and hypertension. NOS1 SNP rs3782218 showed the most consistent association with both phenotypes, odds ratio 0.59 (95% confidence interval 0.44-0.80) and 0.81 (0.67-0.97) per T-allele for CHD and hypertension respectively. For CHD, another NOS1 SNP (rs2682826) and a NOS3 SNP (rs1549758) also showed effect. For hypertension associations were seen for additional SNPs including NOS3 SNP rs3918226, previously associated with hypertension in genome-wide association study (GWAS) data.
We found a previously unreported association between NOS1 SNP rs3782218 and both CHD and hypertension, and confirmed NOS1 as the most important NOS risk gene for CHD. In contrast, variants in all three NOS genes were seen to be associated with hypertension in the same source population.
一氧化氮合酶（NOS）存在三种不同的同工型，每种同工型都由特定的基因编码：神经元型 NOS（NOS1 基因）、诱导型 NOS（NOS2 基因）和内皮型 NOS（NOS3 基因）。NOS 基因中的单核苷酸多态性（SNP）与心血管病理学有关。我们旨在使用一组在 3 个基因中具有良好覆盖度的标记 SNP，全面研究哪些 NOS 基因变异与冠心病（CHD）和高血压相关性最强。
对 560 例 CHD 病例和随机选择的 2791 例人群对照进行了 NOS 基因 58 个 SNP 的基因分型。收缩压≥140mmHg、舒张压≥90mmHg 或服用降压药物的对照个体被定义为高血压。采用结构化逐步逻辑回归方法选择与 CHD 和高血压相关性最强的 SNP。NOS1 基因 SNP rs3782218 与两种表型的相关性最为一致，T 等位基因每增加一个，CHD 的比值比（OR）为 0.59（95%置信区间为 0.44-0.80），高血压的 OR 为 0.81（0.67-0.97）。对于 CHD，NOS1 基因的另一个 SNP（rs2682826）和 NOS3 基因的一个 SNP（rs1549758）也显示出效果。对于高血压，还观察到包括 NOS3 基因 SNP rs3918226 在内的其他 SNP 的相关性，该 SNP 先前与全基因组关联研究（GWAS）数据中的高血压相关。
我们发现了 NOS1 基因 SNP rs3782218 与 CHD 和高血压之间以前未报道的关联，并证实 NOS1 是 CHD 最重要的 NOS 风险基因。相比之下，在同一来源人群中，所有三个 NOS 基因的变异都与高血压有关。
