T-786C Polymorphism in Endothelial NO Synthase Gene Affects Cerebral Circulation in Smokers

Abstract

Abstract-Effects of smoking on white matter lesions, such as lacunar infarction and leukoaraiosis, are still controversial.We hypothesized that the endothelial NO synthase (eNOS) genotype was a modulating factor for the effect of smoking on cerebral circulation. We took a cross-sectional population from the participants of a health examination to study the effects of smoking and a single-nucleotide polymorphism in the eNOS gene, T-786C. Smokers and nonsmokers were defined as having a smoking index (cigarettes per day times years) of Ն200 and 0, respectively. One hundred sixty-six male nonsmokers and 344 male smokers were recruited. Cerebral blood flow was measured by the 133 Xe inhalation method. Genotyping of T-786C was performed by using a newly developed allele-specific polymerase chain reaction. Smokers were exposed to greater oxidative stress, as estimated by urinary F 2 -isoprostane excretion. In smokers, CC homozygotes of T-786C showed a significant decrease of cerebral blood flow (56.6Ϯ13.3, 57.6Ϯ11.5, and 44.0Ϯ7.2 mL/min per 100 g tissue for TT, TC, and CC, respectively; Pϭ0.03 by ANOVA) and a significant increase of cerebrovascular resistance, whereas the eNOS genotype did not affect these parameters in nonsmokers. This result indicated that the eNOS genotype could modify cerebrovascular circulation in a general population by potentiating the adverse effect of smoking. Key Words: nitric oxide synthase Ⅲ polymorphism Ⅲ cross-sectional studies Ⅲ cerebral circulation S moking is an established risk factor for cardiovascular diseases. However, the adverse effect of smoking is controversial in some areas of cerebrovascular disease, such as lacunar infarction and white matter changes. 1-7 Such inconsistency may imply the importance of other environmental or genetic factors in modifying the effects of smoking. Because lacunar infarction and white matter changes are based on occlusive changes in small arteries perforating into the white matter and are characterized by decreased cerebral blood flow (CBF) and increased cerebrovascular resistance (CVR), the endothelial NO synthase (eNOS) gene is a good candidate for such a factor; eNOS constitutively produces NO, a potent vasodilator as well as an antitrophic factor for the arterial wall. 8 -11 Several reports have indicated that eNOS plays an essential role in the regulation of basal CBF in humans and in mice. 9,10 Furthermore, because smoking antagonizes the action of NO through the induction of oxidative stress, 12 it is logical to hypothesize that genetic alteration of eNOS activity may be a modifier of the effect of smoking on the cerebral circulation.Recently, the eNOS gene was studied extensively for genetic polymorphisms to elucidate its genetic role in cardiovascular diseases. As a result, a single-nucleotide polymorphism (SNP) in the promoter region, T-786C, was found to modify the promoter activity in vitro. 13 In addition, this SNP and a 27-bp repeat polymorphism in intron 4, called ecNOS4 a/b, were reported to influence eNOS mRNA and protein levels ...

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

“…This could cause -786T-C mutation leading to a profound impairment of vasodilation, which could result in impaired insulin-mediated glucose uptake in the whole body. A recent study indicated that in smokers -786C homozygote shows a decrease of cerebrovascular circulation [29]. Our study showed that the Glu298Asp mutation had a tendency of impaired insulin-mediated glucose uptake (Table 3).…”

Effects of Six Functional SNPs on the Urinary 8-Isoprostane Level in a General Japanese Population; Shimane COHRE Study

“…The genotype and allele frequencies were not significantly different between the two regions studied. Allele frequencies of the four SNPs in the p22phox, eNOS, LpPLA2 and PON1 genes in these populations were similar to those in the public database (www.ncbi.nim.nih.gov/ projects/SNP) and/or in the previous reports [20][21][22]. In contrast, the both populations had substantially greater frequency of the minor allele for MTHFR C677T, when compared with those in a previous report on Japanese [23].…”

Association of Endothelial Nitric Oxide Synthase Gene Polymor-phisms with Early-Onset Ischemic Stroke in South Indians

“…Smoking has been the main focus of attention, particularly in studies of T-786C polymorphisms in Asian populations. Among smokers, homozygosity for the -786C allele has been shown to be associated with lower cerebral blood flow as well as higher cerebral vascular resistance in comparison with -786T allele carriers 34) . In contrast, the results of our study indicate that the wild genotype of T-786C increases the risk of stroke in smokers and alcohol consumers.…”