Endothelial Nitric Oxide Synthase G894T Research Articles

The effect of endothelial Nitric Oxide Synthase G894T and T786C polymorphisms on Hypoxia-Inducible Factor-1 alpha expression in Sickle Cell Disease

Hypoxia-Inducible Factor-1α (HIF-1α) expression is upregulated in Sickle Cell Disease (SCD) and correlates with various laboratory markers of disease severity. Nitric Oxide plays a pivotal role in SCD pathophysiology and endothelial Nitric Oxide Synthase (NOS3) polymorphisms affect prognosis and laboratory parameters. This study questions the effect of NOS3 G894T and T786C polymorphisms on HIF-1α expression in SCD. We show that G894T polymorphism is a significant predictor of HIF-1α expression. Its effect is exerted independently of hemolysis/hemoglobin fragment concentrations, as shown in multiple regression analysis. Our results establish a novel modulator of HIF-1α expression on the mRNA level and indirectly support the role of nitric oxide in the pathophysiology of SCD.

Study of the Relation between Endothelial Nitric Oxide Synthase G894T Gene Variants and Occurrence of Type II Hepatorenal Syndrome

Background and study aim: The progress of hepatorenal syndrome (HRS) in hepatic patients is not yet understood. Nitric oxide level, through its impact on haemodynamic circulation, may be engaged in the progress of the disease. Our study expected to clarify the possible role of eNOS G894T in decompensated liver cirrhosis and HRS and its relationship with nitrite level. Methods: Study included 80 cirrhotic patients (40 decompensated cirrhotic and 40 HRS) and 40 healthy participants as controls. Renal and liver function tests, CBC, serum electrolytes, plasma nitrite and eNOS G894T by real-time PCR were surveyed. Results: There were higher frequencies of TT and GT genotypes of eNOS G894T versus GG in both cirrhotic (22.5% and 50% respectively) and HRS (30% and 45% respectively) than in controls (10% and 30%) (P=0.007). T allele was more prevalent than G allele in cirrhotic (47.5%) and HRS (52.5%) patients compared to controls (25.0%) (P=0.001). TT and GT genotypes increase risk of cirrhosis by OR 4.909 [95% CI: 1.24 – 19.46] and OR 3.636 [95% CI: 1.32 – 9.99] and HRS OR7.200 [95% CI: 1.86 – 27.77] and 3.600[95% CI: 1.27 – 10.7] respectively. T allele can increase risk of cirrhosis by OR 2.714 [95% CI: 1.39 – 5.30] and HRS OR 3.316 [95% CI: 1.70 – 6.48]. Clear connections were observed between TT genotype and lower plasma nitrite level (P<0.001). Conclusion: Mutant variants of eNOS G894T gene in cirrhotic and HRS patients from controls could partially explain the progress to decompensation and HRS in liver cirrhosis.

Research Article Endothelial nitric oxide synthase G894T polymorphism increases the risk of infertility in women with endometriosis

Research Article Endothelial nitric oxide synthase G894T polymorphism increases the risk of infertility in women with endometriosis

Prooxidant-antioxidant balance depending on endothelial nitric oxide synthase G894T polymorphism

The aim of the study was to assess the prooxidant-antioxidant balance depending on endothelial nitric oxide synthase G894T polymorphism. The frequency distribution of alleles and genotypes of G894T polymorphism, nitrite concentration, hydrogen sulphide, lipid peroxidation products (diene conjugates, malonic dialdehyde), antioxidants (reduced glutathione, catalase, ceruloplasmin, retinol) were determined in venous blood of healthy males. The incidence of the GG genotype was 49.1%, GT - 44.2%, TT - 6.7%. The level of malonic dialdehyde in erythrocytes with the GG genotype is 16.8% lower than in the genotype GT. The concentration of hydrogen sulphide in the blood with the GG genotype was 27.5 [18,2; 32,5] mM, GT - 28.6 [22.9; 33.8] mM, TT - 36.3 [33.8; 42.5] mM. The content of total nitrites in plasma with the GG genotype was 10.4 [9,0; 12,5] mM, GT - 10.4 [8.9; 11.8] mM, TT - 9.4 [8.8; 9.8] mM. The genotype GG causes a lower level of malonic dialdehyde in comparison with the heterozygous genotype. The G894T polymorphism allele T is associated with a low content of total nitrites in the plasma and a high concentration of hydrogen sulfide. The data obtained suggest that if the oxygen supply of the organism is impaired, the endothelial nitric oxide synthase G894T polymorphism may be important for the oxidative stress development.

Heart failure and endothelial nitric oxide synthase G894T gene polymorphism frequency variations within ancestries

The G894T polymorphism in endothelial nitric oxide synthase enzyme gene plays an important role in heart failure (HF) and its frequency varies among populations. We investigated this association in highly admixed samples in terms of ancestry. The cohort included 210 HF patients and 106 healthy individuals. Self-reported race and NYHA class were analyzed for HF patients. G894T polymorphism was analyzed by polymerase chain reaction (PCR) and by restriction fragment length polymorphism technique. Ancestry was estimated using a PCR reaction containing 46 autosomal ancestry informative markers and an analysis by capillary electrophoresis. The GG homozygous genotype had a higher frequency in HF patients (63.8%) than in healthy individuals (48.1%), showing an increased chance (odds ratio 1.90, 95% confidence interval 1.18–3.05). The ancestry profiles in patients and controls were similar, with a major European contribution (57.1% and 63.2%), followed by African (30.2% and 24.0%) and Native American (12.7% and 12.8%), without a significant difference between both samples (p = 0.28). The GG genotype is associated to HF prognosis, and this association remains present in highly admixed sample groups.

Association of Nitric Oxide Levels and Endothelial Nitric Oxide Synthase G894T Polymorphism with Coronary Artery Disease in the Iranian Population.

Purpose:The endothelial nitric oxide synthase (eNOS) G894T polymorphism has been reported to cause endothelial dysfunction and may have a role in the development of coronary artery disease (CAD). The aim of the present study was to investigate the association of eNOS G894T genetic polymorphism and plasma levels of nitric oxide (NO) with CAD risk in an Iranian population.Materials and Methods:We studied 200 patients with angiographically documented CAD and 100 matched controls. Analysis of G894T genetic polymorphism of eNOS was performed by polymerase chain reaction-restriction fragment length polymorphism method. Plasma levels of NO were determined using Griess method. Biochemical analysis was conducted by routine colorimetric methods.Results:Plasma levels of NO were significantly lower in CAD patients than control subjects (41.60±12.70 vs. 55.48±16.57, P=0.001). Also, the mean plasma levels of NO were significantly lower in T allele carriers of eNOS G894T polymorphism than G allele carriers (P<0.001). The genotype distribution and minor T allele frequency of eNOS G894T polymorphism significantly differed between CAD patients and control subjects (P<0.05). However, no significant association was found between the eNOS G894T polymorphism and the severity of CAD (number of diseased vessel) or the lipid profile of CAD patients (P>0.05).Conclusion:Reduced plasma level of NO is associated with increased risk of CAD in our population. Moreover, eNOS G894T polymorphism is a significant risk factor for CAD development via reducing the plasma levels of NO. However, eNOS G894T polymorphism is not a contributing factor for the severity of CAD.

Association between Endothelial nitric oxide synthase G894T gene polymorphism and risk of ischemic stroke in North Indian population: a case-control study

Background and purpose: Stroke is a multi-factorial disease influenced by both genetic and environmental factors. The aim of this case-control study was to determine the association between Endothelial Nitric Oxide Synthase G894T (rs1799983) gene polymorphism and susceptibility to ischemic stroke (IS) in North Indian population.Methods: In this present case-control study, genotyping was performed by using Polymerase chain reaction – Restriction fragment length polymorphism (PCR-RFLP) method for 250 IS patients and 250 age and sex matched controls. PCR results were confirmed by DNA sequencing. Frequency distribution of genotypes and alleles were compared between cases and controls using conditional logistic regression.Results: Hypertension, Diabetes, Dyslipidemia, Low Socioeconomic Status and Family History of Stroke were found to be independent risk factors for IS. Mean age of cases and controls were 52.83 ± 12.59 and 50.97 ± 12.70 years. Multivariate logistic regression analysis showed a significant association between eNOS G894T (rs1799983) polymorphism and risk of IS [OR = 1.57; 95%CI 1.05–2.37; p = 0.028] under dominant model. Based on Trial of Org 10172 in Acute Stroke Treatment classification, an independent association of large vessel disease (LVD) was observed with the risk of IS under the dominant [OR = 2.09; 95% CI 1.17–3.75; p = 0.01] and recessive [4.09 95% CI 1.06–15.68; p = 0.04] models. All the observed genotype frequencies were in accordance with the Hardy–Weinberg equilibrium (HWE) in both cases and controls.Conclusion: The findings of the present study suggest that polymorphism in G894T position of eNOS gene might be a risk factor for IS mainly for LVD stroke subtype in North Indian population. Further large prospective studies are required to confirm these findings.

Endothelial nitric oxide synthase g894t (rs1799983) gene polymorphism in polish athletes

Abstract The NOS3 gene has been associated with athletic endurance performance and elite power athletic status. With respect to NOS3 G894T and its relation to athletic performance or status, results across various studies have not been consistent. Therefore, the lack of consistency among previous studies prompted us to design a case-control study in a Polish Caucasian population to examine the relationship between the NOS3 G894T polymorphism and athletes' status, i.e. type and intensity of exercise performed (poweroriented, “mixed” power/endurance activity, endurance-oriented) and the possible association between the G894T variant and athletic performance. The case-control study was performed in a group of 360 Polish athletes (cases) of the highest nationally competitive standard (male n=156 and female n=67) and 191 unrelated, sedentary control subjects. The G894T genotype and allele distributions differed significantly between power-oriented (P=0.009, P=0.003), “mixed” (P=0.021, P=0.009), endurance (P=0.043, P=0.014) athletes when compared to control subjects (P values for genotypes and alleles, respectively). There were no significant differences between elite and sub-elite athletes in any group. The over-representation of the GG genotype and G allele in all athletes suggests that the G894 allele may favour all types of sports, however, the strongest predisposition was seen among power-oriented athletes.

Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Essential Hypertension in the Chinese Population: a Meta-Analysis Involving 11,248 Subjects

The endothelial nitric oxide synthase (eNOS) G894T gene polymorphism has been suggested to be linked to the risk of essential hypertension (EH), however the results are still debatable. To assess the association between eNOS G894T gene polymorphism and EH, such electronic databases as Pubmed, Embase, Web of Science, China Biological Medicine Database (CBMD) and China National Knowledge Infrastructure (CNKI) were searched. The selection criteria were as follows: a) Evaluation of the association of eNOS G894T gene polymorphism and EH. b) EH diagnosis in compliance with EH diagnosis criteria of the World Health Organization (WHO) in 1999. c) The study results were in line with the Hardy-Weinberg equilibrium (HWE). In 23 separate studies with 11,248 subjects the relation between eNOS G894T gene polymorphism and EH was analyzed by current meta-analysis. Random effect model was used to calculate the pooled odds ratio (ORs) and its corresponding 95% confidence interval (95% CI). In this eNOS G894T gene polymorphism and EH meta-analysis in the Chinese population, the distribution of T allele frequency was 0.154 for EH group and 0.128 for the control group. A significant association was found between G894T gene polymorphism and EH (p=0.0007). The pooled OR for the distribution frequency of T allele was 1.33 (95% CI:1.13-1.56, P(heterogeneity) <0.00001). In the stratified analysis by ethnicity, there was a significant association in Han subgroup (p=0.005). The pooled OR for the distribution frequency of T allele was 1.31 (95% CI:1.09-1.59, P(heterogeneity) <0.00001). No significant increased risk for EH was found in the non-Han subgroup (p=0.08). In the current meta-analysis, T allele of eNOS G894T gene was suggested to be related to the increased risk of EH in the Chinese population, particularly in those of Han ethnicity.

Association Analysis of Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Erectile Dysfunction Complaints in a Population-Based Survey

Erectile dysfunction (ED) is a common disorder leading to a serious, negative impact on the quality of the patient's life. The gene encoding endothelial nitric oxide synthase (eNOS) is an interesting candidate gene for understanding the physiopathology of ED, as it is involved in the catalytic production of nitric oxide (NO), the neurotransmitter that plays a critical role in penile tumescence and erection. To evaluate a potential association between the G894T polymorphism in the eNOS gene and ED complaints in a population-based sample in São Paulo, Brazil. The prevalence of ED complaints was estimated according to the answer to the question "How would you describe your ability to get and keep an erection that is adequate for satisfactory intercourse?" ED was considered to be present if the response was "sometimes" or "never." A total of 449 men were enrolled in the study and answered an eight-item questionnaire to ascertain sexual performance/ED and satisfaction. The eNOS G894T polymorphism was genotyped using a standard polymerase chain reaction method. Univariate analysis demonstrated that ED was associated with diabetes, hypertension, sleep apnea severity, increasing age and body mass index, as well as testosterone levels (P < 0.05). Forward multiple regression models indicated that age was the only independent factor associated with ED in this population (odds ratio = 1.09; 95% CI 1.06-1.11; P < 0.0001). Genotypic and allelic analyses provided no evidence for an association between this polymorphism and the risk for ED complaints in this sample. Population stratification did not affect the association test results. This is the first study to examine the effect of polymorphisms in the eNOS gene and the risk for ED utilizing a case-control approach in the Brazilian population. Our results do not support a major role for eNOS gene polymorphisms in ED in this population.

Association Analysis of Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Erectile Dysfunction Complaints in a Population-Based Survey

Association Analysis of Endothelial Nitric Oxide Synthase G894T Gene Polymorphism and Erectile Dysfunction Complaints in a Population-Based Survey

Endothelial nitric oxide synthase G894T gene polymorphism and response to skin reactive hyperemia

Post occlusive skin reactive hyperemia (PORH) is a tool used to assess microcirculation. Endothelial nitric oxide synthase (eNOS) mediates nitric oxide (NO) production; polymorphism of the eNOS gene may affect response to the PORH process. This study aims to determine whether eNOS G894T gene polymorphism affects response to skin PORH. 230 normotensive male and females between 18 and 40 years participated in this cross-sectional study. 170 subjects were of the homozygous GG genotype, whereas 60 were of the GT genotype. Skin PORH was performed by occlusion of the upper arm at 200 mm Hg for 3 min. Skin perfusion and temperature were monitored before, during and after occlusion release using the laser Doppler fluximetry. There were no significant differences between genotypes in their baseline blood pressure, serum cholesterol, BMI and age. Maximum change in perfusion after occlusion release (PORHmax) for the GG and GT genotypes were not significantly different at 50.15 ± 1.29 vs. 47.92 ± 2.17 AU; ANCOVA, p = 0.351. Peak perfusion (PORHpeak) were also not significantly different between the two genotypes (61.23 ± 1.36 vs. 57.72 ± 2.32 AU; p = 0.169). Minimum baseline perfusion were however higher in the GG compared to the GT genotype (10.83 ± 0.29 vs. 9.61 ± 0.50, p = 0.029). We conclude that microvascular reactivity, assessed by change in perfusion after temporary ischemia was not significantly different between the GG and GT genotypes of the eNOS G894T gene. eNOS 894T allele carriers however, have lower baseline perfusion compared to the homozygous G894 allele carrier.

The association of endothelial nitric oxide synthase G894T polymorphism with C-reactive protein level and metabolic syndrome in a Chinese study group

Some studies have reported a possible relationship between endothelial nitric oxide synthase (eNOS) and metabolic syndrome (MS), which is associated with an increased risk for cardiovascular disease. A recent meta-analysis study found the eNOS G894T polymorphism to be associated with ischemic heart disease. Here, we examine the association of eNOS G894T polymorphism with MS in a Chinese population (n = 397). The eNOS T+ (TT and GT) genotypes (56.92% vs 38.86%; odds ratio, 2.08; 95% confidence interval, 1.21-3.56; P = .007) and T allele (33.08% vs 23.34%; odds ratio, 1.62; 95% confidence interval, 1.08-2.44; P = .019) were significantly more frequent in subjects who had MS. Furthermore, subjects with eNOS T+ genotypes had significantly higher plasma C-reactive protein levels as compared with GG subjects ( P = .004). This study shows that, in a Chinese population, eNOS G894T polymorphism is associated with an elevated C-reactive protein level and MS.

Endothelial nitric oxide synthase G894T (Glu298Asp) polymorphism was predictive of glycemic status in a 5-year prospective study of Chinese subjects with impaired glucose tolerance

Subjects with impaired glucose tolerance (IGT) have a high risk of developing type 2 diabetes mellitus (DM) and its related complications. However, both environmental and genetic factors may influence the progression or regression of hyperglycemia. Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been associated with DM in cross-sectional studies, but their predictive values in glycemic progression are not known. We examined the relationship of the eNOS promoter −T786C (−T786C), intron 4 variable tandem repeat (in4a/b), and exon 7 G894T (G894T) polymorphisms, and their haplotypes, with the long-term glycemic outcome in a Chinese cohort with IGT. Two hundred fifty-six Chinese subjects with IGT at baseline participated in a 5-year follow-up study to assess their glycemic outcome. Each individual was genotyped for the above-mentioned polymorphisms. At 5 years, 40.2% of the subjects had reverted to normal glucose tolerance; 39.9% remained in IGT/impaired fasting glucose and 19.9% had developed DM. A significant gene effect of exon 7 G894T polymorphism on glycemic status at 5 years was demonstrated, with carriers of T 894 being more likely to have persistent hyperglycemia compared with GG subjects ( P = .003). On stepwise logistic regression analysis, the presence of the T allele remained a significant risk factor for persistent hyperglycemia (odds ratio, 2.72; 95% confidence interval, 1.36-5.99; T+ vs GG; P = .013), together with male sex, high body mass index, and high 2-hour glucose at baseline. No significant effect of −T786C or in4a/b polymorphism on fifth-year glycemic status was observed. The eNOS G894T polymorphism appears to be predictive of persistent hyperglycemia in Chinese subjects with IGT.

Gene-Gene and Gene-Environment Interplay Represent Specific Susceptibility for Different Types of Ischaemic Stroke and Leukoaraiosis

Stroke is a very frequent entity. It is the third leading cause of death and the leading cause of adult disability in the developed world. At a population level, the common sporadic form of ischaemic stroke is underpinned by both environmental and genetic risk factors. Typically, in clinical practice, environmental risk factors such as hypertension, diabetes mellitus, smoking, alcohol consumption, and other factors, are usually considered to be more important than genetic factors. However, it is the interplay of both environmental and common genetic factors [such as the Leiden V, methylenetetrahydrofolate reductase C677T, apolipopotein E 4, endothelial nitric oxide synthase G894T, angiotensin-converting enzyme I/D and angiotensin II type 1 receptor A1166C mutations and polymorphisms] that leads to the development of ischaemic stroke. Indeed, a complex network of interactions between genetic factors and clinical risk factors can be supposed. This review evaluates the possible roles of gene-gene and gene-environment interactions concerning the above genetic factors in the evolution of ischaemic stroke and leukoaraiosis. A knowledge of the specific genetic patterns which are associated with a significant risk of ischaemic stroke or leukoaraiosis may also draw attention to a large population at an increased risk of circulatory disorders. This may facilitate the choice of more effective and specific prevention on the basis of the genotype.

Endothelial nitric oxide synthase G894T gene polymorphism in Chilean subjects with coronary artery disease and controls

Background Nitric oxide (NO) from the endothelium, produced by oxidation of l-arginine to l-citruline for the action at the endothelial nitric oxide synthase (eNOS), is considered an important atheroprotective factor. The Glu298Asp (G894T) polymorphic variant of the eNOS gene has been implicated in the development of coronary artery disease (CAD). We investigated the association between occurrence of CAD documented by angiography and the G894T polymorphism of the NOS3 gene in Chilean individuals. Methods A total of 112 unrelated patients with diagnosis of CAD and 72 controls were included in this study. G894T gene polymorphism was analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results The frequency of TT homozygous genotype for G894T polymorphism was 7% in CAD patients and 1% in the control group. However, the genotype distribution and allele frequencies were not significantly different between CAD and control subjects ( P > 0.05). Moreover, the odds ratio for CAD associated with the T variant failed to reach statistical significance (OR = 1.5; 95% CI: 0.87–2.59, P > 0.05). Conclusion These findings suggest that the G894T polymorphism of the eNOS gene was not associated with CAD in Chilean individuals.