Common Variants of the Endothelial Nitric Oxide Synthase Gene and the Risk of Coronary Heart Disease Among U.S. Diabetic Men

Abstract

Endothelial nitric oxide synthase (eNOS) gene represents a promising candidate gene for coronary heart disease (CHD) because of its impact on eNOS activity. We systematically examined the associations of eight variants of the eNOS gene (two potentially functional variants [؊786T>C and Glu298Asp] and six tagging single nucleotide polymorphisms) with CHD risk in a large cohort of diabetic patients. Among 861 diabetic men (>97% Caucasian) from the Health Professionals Follow-Up Study, 220 developed CHD, and 641 men without cardiovascular disease were used as control subjects. Genotype distributions of ؊786T>C and Glu298Asp polymorphisms were not significantly different between case and control subjects. CHD risk was significantly higher among men with the variant allele at the rs1541861 locus (intron 8 A/C) than men without it (adjusted odds ratio 1.5 [95% confidence interval 1.1-2.1]). Moreover, among control subjects, plasma soluble vascular cell adhesion molecule concentrations were significantly higher among carriers of this allele (P 0.019) and carriers of the variant allele of the ؊786T>C (P 0.010), or the Glu298Asp polymorphism (P 0.002), compared with noncarriers. In conclusion, our data suggested that ؊786T>C, Glu298Asp, and an intron 8 polymorphism of the eNOS gene are potentially involved in the atherogenic pathway among U.S. diabetic men. (1), and inhibiting the proliferation of smooth muscle cells (2). Endothelial-derived NO is synthesized from L-arginine by NO synthase encoded by endothelial NO synthase (eNOS or NOS3) gene, mapped on chromosome 7q36 (3). The eNOS gene knockout mouse was demonstrated to have an increased susceptibility to develop atherosclerosis independent of blood pressure changes (4). Both ex vivo and in vivo eNOS gene transfer to atherosclerotic arteries can improve acetycholine-induced endothelium-dependent vasodilation (5-10).The association between several polymorphisms of the eNOS gene and coronary heart disease (CHD) risk has been studied recently. In particular, the Ϫ786TϾC polymorphism in the 5Ј-flanking region and the Glu298Asp polymorphism in exon 7 have received the most attention; these two polymorphisms have been associated with alterations in eNOS activity in experimental studies (11)(12)(13)(14) and with the existence, severity, and progression of CHD in some, although not all, epidemiological studies (12,(15)(16)(17). The association of these potentially functional polymorphisms with CHD risk has not been well studied among diabetic patients. Furthermore, we are unaware of studies that have systematically investigated the association of variants of the eNOS gene with CHD risk. In the present study, we examined associations of the two potentially functional single nucleotide polymorphisms (SNPs) and tagging SNPs of the eNOS gene with CHD risk among diabetic men. The associations of these eNOS SNPs with circulating levels of soluble VCAM-1 (sVCAM-1) and ICAM-1 were also examined. RESEARCH DESIGN AND METHODSThe Health Professionals Follow-Up Study is a prospective coho...

Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis

“…On the contrary, our results differed from those of Zhang et al (47), who observed no association of Glu 298 Asp polymorphism and CAD risk in diabetic men. To try to reconcile the latter and our present results, it must be considered that in type 2 diabetes mellitus, other risk factors are more prevalent and could mask the influence of NOS3 variants on CAD.…”

“…The association between several polymorphisms of the NOS3 gene and CAD and restenosis risks has been previously studied (2,5,6,8,25,45). Zhang et al (47) did observe a potential involvement of 786T3 C, Glu 298 Asp, and intron 8 single-nucleotide polymorphism (SNP) variants in the atherogenic process in diabetic subjects with CAD. Other studies showed that homozygosity of Glu 298 Asp and Ϫ786T3 C polymorphisms of the NOS3 gene represented an independent risk factor for in-stent restenosis (12,40), and the 894G3 T polymorphism of NOS3 gene was associated with an increased risk of death and/or myocardial infarction within 1 yr after stent placement (13).…”

Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques?

“…87 Glycoxidation and lipid oxidation are thought to contribute to atherosclerosis and, therefore, it may be expected that alleles for genes that protect cells from oxidation damage may retard cardiovascular disease associated with diabetes. Common variants in the paraoxonase 1 gene 88 and the endothelial nitric oxide synthase gene 89 were shown to modulate risk of coronary heart disease among subjects with type 2 diabetes. The important contribution to atherosclerosis of RAGE has been shown in several studies of diabetic and nondiabetic mice.…”

Association of endothelial nitric oxide synthase polymorphisms with coronary artery disease in Korean individuals with or without diabetes mellitus

“…to our knowledge, this is the first report to determine the association of CAD with three eNOS polymorphisms by comparing four subgroups divided according to both cad and t2dm. Zhang et al (24) examined eNOS variants and the risks of coronary heart disease among diabetic men in the uS and found that the genotype distributions of -786t>c and 894G>t were not significantly different among the men with or without coronary heart disease, but non-diabetic samples were not included in their study. We observed that the allele frequencies of eNOS -786T>C, 4a4b and 894G>T were not significantly different between the non-diabetic cad patients and the non-diabetic controls (Table II).…”