Endothelial Nitric Oxide Synthase Polymorphisms Research Articles

Involvement of Total Antioxidant Activity and eNOS Gene rs1799983/ rs2070744 Polymorphisms in Breast Carcinogenesis

Globally, breast cancer is the common malignancy affecting women and understanding its associated molecular events could help in disease prevention and management strategies. The present study was set to investigate an association between total antioxidant capacity (TAC) and endothelial nitric oxide synthase (eNOS) polymorphisms with breast cancer. For this purpose, 100 subjects were participated in this work, including 50 female patients diagnosed with breast cancer recruited from Oncology hospital, Baghdad - Iraq and 50 healthy women as a control group. The concentration of antioxidants was measured in the serums collected from blood samples of breast cancer patients and healthy controls. While eNOS SNPs (rs1799983, G894T and rs2070744, T 786C) were assessed using TaqMan SNP genotyping and utilising genomic DNA extracted from the participants. The results showed that the antioxidants levels were significantly (P˂0.0001) reduced in blood samples of breast cancer patients in comparison to that of that healthy controls (0.144± 0.097 and 0.587±0.239 respectively). Additionally, the homozygous GG genotype G894T (rs1799983) could retain beneficial impact for the protection from breast cancer potential. While SNP genotyping results showed that both of the homozygous CC and heterozygous TC genotypes (rs2070744 T >C SNP) seem to contribute to the susceptibility of breast cancer development in the investigated set of patients. Overall, the present study findings suggest an association between reduced antioxidant capacity and eNOS gene polymorphisms in breast carcinogenesis.

Prognostic significance of three endothelial nitric oxide synthase (eNOS) polymorphisms and metabolic syndrome (MetS) in patients with colorectal cancer.

Polymorphisms of endothelial nitric oxide synthases (eNOS) have been associated with cancer susceptibility. Also, metabolic syndrome is associated with cancer malignancy. However, the effect of eNOS polymorphisms and metabolic syndrome on colorectal cancer (CRC) prognosis remains unclear. To investigated whether three genetic polymorphisms (-786T > C rs2070744, 4a4b rs869109213, and 894G > T rs1799983) in the eNOS and metabolic syndrome (MetS) were associated with CRC patient survival. We genotyped three polymorphisms of eNOS (-786T > C, 4a4b, and 894G > T) in 312 CRC cases from the Korean population by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Although the three eNOS polymorphisms were not causative of MetS, the TT genotype of the 894G > T polymorphism was associated with a worse survival rate compared with the GG genotype in the CRC group with MetS than in the CRC group without MetS (5-years survival; adjusted HR = 54.777; 95% CI 5.073-591.487 and RFS; adjusted HR = 14.909; 95% CI 1.571-141.528). The eNOS polymorphisms were not associated with metabolic syndrome prevalence in CRC patients. However, our findings suggest that the eNOS 894G > T polymorphism with MetS was associated with poor clinical outcomes.

Are P-glycoprotein (ABCB1/MDR1) and endothelial nitric oxide synthase (eNOS) polymorphisms related to severity of the coronary artery disease?

Background/Aim: Atherosclerotic cardiovascular disease is one of the most common causes of morbidity and mortality in developed countries. Genetic and environmental factors are associated with atherosclerosis development. Some single nucleotide polymorphisms have also been directly related to atherosclerosis, for example, polymorphisms that reduce nitric oxide (NO) levels and/or activity have been linked to atherosclerotic diseases. However, the multidrug resistance gene 1 (MDR-1) polymorphism is related to repeated cardiovascular events. This study aimed to investigate the relationship between MDR-1 and endothelial NO synthase (e-NOS) polymorphism and severe coronary artery disease (CAD). Methods: In total, 90 patients presenting with acute coronary syndrome were included in this cross-sectional study. Patients with at least > 70% stenosis in ≥ 2 coronary vessels were defined as severe CAD (Group 1), while those with this same level of involvement in < 2 vessels were diagnosed with single-vessel disease (Group 2). MDR 3435C-T and eNOS T-786C were determined by polymerase chain reaction (PCR) amplification. Comparison of parametric and nonparametric values between the two groups was performed using the Student’s t- or Mann–Whitney U test. Categorical variables were analyzed using the χ2 test. Risk estimations for the association of severe CAD with the polymorphisms were calculated using odds ratio (OR) and 95% confidence intervals by comparing the genotypic combinations. Results: Baseline demographic parameters were similar in both groups, except for the presence of DM and glucose level. T allele of MDR was 42% and 40% in groups 1 and 2, respectively (OR = 1.12). The C allele of eNOS was 34% and 30% in groups 1 and 2, respectively (OR = 1.16). Fourteen and 15 patients (40% and 27%, respectively) had both T and C alleles in patients in groups 1 and 2, respectively (OR = 1.77). All P-values were > 0.05. Conclusion: This study is the first one that shows that MDR1 and e-NOS polymorphisms are frequent in patients with ≥ 2 vessel disease and may be associated with severe CAD.

Endothelial nitric oxide synthase (Glu298Asp) polymorphism is associated significantly with ischemic stroke presenting with seizures and altered sensorium

Endothelial nitric oxide synthase (eNOS) is an enzymatic marker whose genetic polymorphism might predispose to acute ischemic stroke (AIS) via vascular endothelial dysfunction. It has potential role in atherosclerosis, making it a plausible risk factor for stroke. Prior studies have failed to prove a conclusive relationship between eNOS polymorphism and AIS. The aim of this study is to find an association between the presence of eNOS polymorphism (Glu298Asp) and the risk of developing AIS.

Endothelial nitric oxide synthase polymorphism and venous thromboembolism: A meta-analysis of 9 studies involving 3993 subjects.

Endothelial nitric oxide synthase (eNOS) polymorphism may influence the risk of venous thromboembolism (VTE). However, data from published studies with low statistical power are inconclusive. The present meta-analysis aimed to assess the relationship between eNOS polymorphism and the risk of VTE. Case-control studies evaluating the association between the eNOS polymorphism and VTE were searched in PubMed, Embase, Web of Science, Google Scholar, Wanfang, Chinese National Knowledge Infrastructure (CNKI), the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and Chinese Biomedical Literature Database (CBM). A total of 1588 cases and 2405 controls from 9 studies were included in the analysis. The results showed that eNOS G894T polymorphism was related to VTE susceptibility and the difference was statistically significant [T vs G: OR = 1.41, 95% CI (1.13, 1.75), P = 0.002; TT + GG vs TG: OR = 0.71, 95% CI (0.60, 0.84), P = 0.000; TT + TG vs GG: OR = 1.45, 95% CI (1.23, 1.70), P = 0.000]. Additionally, eNOS Intron 4 VNTR polymorphism was related to VTE susceptibility and the difference was statistically significant [4b4b vs 4a4a + 4a4b: OR = 2.77, 95% CI (1.01, 7.61), P = 0.048]. ENOS G894T and eNOS Intron 4 VNTR polymorphisms were associated with VTE susceptibility, especially in Asian populations. However, multicenter studies with larger samples should be conducted to further clarify this association and verify our findings.

The role of caveolin-1 and endothelial nitric oxide synthase polymorphisms in susceptibility to prostate cancer.

Caveolin-1(cav-1) is overexpressed in prostate cancer (PC) and is associated with progression of the disease. We investigated the effects of CAV1-T29107A and endothelial nitric oxide synthase (eNOS) G894T polymorphisms on the serum levels of testosterone, NO and prostate-specific antigen (PSA) in patients with PC. We genotyped cav-1 and eNOS genes in 112 PC patients and 150 healthy controls by PCR-RFLP. Serum levels of and were measured using spectrophotometry, and serum levels of testosterone and PSA were measured by ELISA. The frequencies of CAV1 genotypes A/T vs. A/A according to the dominant model AT+TT vs. AA genotype and T allele were significantly higher in PC patients in comparison with the control group and considerably increased the risk of disease by 2.19-, 1.44- and 1.6-fold, respectively. AT+TT genotypes were associated significantly with the increased risk of PC in those with smoking or diabetes by 3.08-fold (P=.004). Individuals carrying concurrently the T allele of CAV1 A29107T and the T allele of eNOS G894T genes had a significantly increased risk of PC by 2.52-fold (P=.009). We did not find any significant relationship between eNOS G894T genotypes and alleles with susceptibility to PC. Our results highlighted the significance of CAV1-T29107A SNP but not (eNOS) G894T in the susceptibility to PC in our the population that we have studied.

Endothelial Nitric Oxide Synthase (Glu298Asp) Polymorphism Is Associated Significantly With Ischemic Stroke Presenting With Seizures And Altered Sensorium (4961)

Endothelial Nitric Oxide Synthase (Glu298Asp) Polymorphism Is Associated Significantly With Ischemic Stroke Presenting With Seizures And Altered Sensorium (4961)

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.

Acute Exercise, Plasma Nitric Oxide, and Blood Pressure in Older Adults With Different Levels of Training Status: The Influence of Polymorphisms of Endothelial Nitric Oxide Synthase.

This study aimed to analyze the acute effect of physical exercise on nitric oxide concentration and blood pressure (BP) in older adults with different levels of training status (TS) and verified the influence of endothelial nitric oxide synthase polymorphisms on these variables. A total of 145 older adults were divided into good TS (G1) and weak TS (G2). Participants were subjected to a 40-minute treadmill walk (40%-60% of maximum oxygen consumption) with BP measurements and blood collections for plasma nitrite and oxidative stress biomarkers at pretest and posttest moments. Data were analyzed by 2-way repeated-measures with Sidak post hoc test (P < .05) and multivariate linear analysis. After acute exercise, G2 showed an increase in oxidative stress biomarkers (P = .008), and both groups showed an increase in systolic BP (P < .001). Polymorphisms 894G > T and intron 4b/a had no association with nitrite and BP. However, -786T > C polymorphism showed an association with reduced systolic and diastolic BP (TT genotype) and increased diastolic BP (TC genotype). Higher TS level was also associated with lower BP. The maintenance of good TS levels may have a protective effect on cardiovascular risks regardless of the genetic profile.

NOS3 Polymorphisms Can Influence the Effect of Multicomponent Training on Blood Pressure, Nitrite Concentration and Physical Fitness in Prehypertensive and Hypertensive Older Adult Women

Associations of endothelial nitric oxide synthase (NOS3) polymorphisms with hypertension and response to exercise training in prehypertensive and hypertensive older adult women remain unclear. This study used a multicomponent program (various capacities and motor skills) in the physical training intervention. It analyzed the influence of NOS3 polymorphisms [−786T > C, 894G > T (Glu298Asp), and intron 4b/a] on the response of blood pressure (BP), nitrite concentration, and physical fitness in older adult women. Fifty-two participants aged between 50 and 80 underwent body mass index, BP, 6-min walk, elbow flexion, and sit and stand-up tests to assess physical fitness. The intervention duration was 12 weeks, twice a week, on non-consecutive days. Each session lasted 90 min, maintaining an intensity between 13 (moderate) and 15 (intense), controlled by the Subjective Effort Perception Scale. Plasma/blood samples were collected to assess nitrite concentration and genotyping. The statistical analysis included Fisher’s exact test and linear mixed-effects models. The multicomponent training’s positive effect was observed with a similar response in both prehypertensive and hypertensive groups. However, carriers of different genotypes demonstrated different responses to training: the decreases in systolic and diastolic BP and increases in nitrite expected from the physical training were smaller in variant genotype than ancestral genotype carriers, especially in the hypertensive group. At positions −786T > C and Glu298Asp, only the ancestral genotypes showed a decrease in diastolic BP (Δ% = −8.1, and Δ% = −6.5, respectively) and an increase on nitrite (Δ% = 19.1, and Δ% = 24.1, respectively) in the hypertensive group. Our results show that the benefits of a multicomponent training intervention seem to be genotype-dependent. It should be possible to consider genetic variants when selecting an exercise treatment intervention.

Association between Endothelial nitric oxide synthase and Hepatic lipase gene polymorphisms with the risk of coronary artery disease in Southern Iran population – A case control study

Coronary artery disease is a multifactorial genetic disease caused by the interaction between genetic and environmental factors. Angiography is the gold standard method for the diagnosis and determining the stage of cardiac disorder. The rs1800588 at the Hepatic Lipase gene and rs1799983 at the endothelial nitric oxide synthase (eNOS) gene are two candidate SNP that result in increased risk of this disease. The aim of this study was to find out the associations of the two mentioned polymorphisms with angiographically proven coronary artery patients in a southern Iranian population. In this study, this two polymorphisms in 287 patients and 229 matched controls were confirmed by angiography and analyzed. Genotype analysis was carried out by PCR and RFLP. Data showed that a significant difference for the eNOS gene polymorphism (p = 0.004) and a non-significant difference for the Hepatic lipase polymorphism (p = 0.261) and increasing severity of angiographic evidences of coronary artery disease were observed. Conclusively the significant association of the G894T with the narrowing of two or three coronary vessels of this patients in an Iranian population have been detected.

Endothelial Nitric Oxide Synthase (Glu298Asp) Polymorphism is Associated Significantly with Ischemic Stroke Presenting with Seizures and Altered Sensorium.

Endothelial nitric oxide synthase (eNOS) is an enzymatic marker whose genetic polymorphism might predispose to acute ischemic stroke (AIS) via vascular endothelial dysfunction. It has a potential role in atherosclerosis, making it a plausible risk factor for stroke. Prior studies have failed to prove a conclusive relationship between eNOS polymorphism and AIS. The aim of this study is to find an association between the presence of eNOS polymorphism (Glu298Asp) and the risk of developing AIS. We recruited 307 subjects including 153 AIS cases and 154 healthy controls. The eNOS (Glu298Asp) polymorphism was identified in EDTA blood by PCR amplification of the target region followed by restriction enzyme digestion, and genotyping on Agarose gel. GG, GT and TT genotypes were obtained. Statistical analysis was done using SPSS software version 20. A significant association was found between the presence of TT genotype and the risk of AIS (Odd's ratio (OR): 2.43, P-value = 0.038). There was no significant association between the TT genotype and the traditional stroke risk factors. However, the TT genotype was significantly associated with the presence of altered consciousness (OR: 5.27, 95% CI: 1.59-17.04, P-value = 0.003) and with the occurrence of seizures at presentation (OR: 7.98, 95% CI: 1.99-32.09, P-value = 0.007). There is a significant association between the presence of eNOSpolymorphism (Glu298Asp) and the risk of AIS, and the TT genotype may predispose to a more severe initial presentation of ischemic stroke.

T786C eNOS polymorphism as risk factor for recurrent myocardial infarction in young and middleaged patients

Objective. To determine the possible role of the endothelial nitric oxide synthase (eNOS) polymorphism T786C (rs 2070744) in developing of recurrent myocardial infarction (MI) in young and middle-aged patients. Materials and methods. 114 patients with acute MI treated with percutaneous coronary intervention and thrombolysis that were admitted to Clinical cardiologic dispensary (Perm city, Russia) were enrolled into a study. Among them there were 28 patients with recurrent MI. The eNOS T786C polymorphism were determined by real-time PCR. Results. In T786C polymorphism of eNOS, compared with the T/T genotype, it was determined that those with T/C has 2,27 fold (95 % CI: 1.01–5.49), and those with the CC genotype has 2.22 times (95 % CI: 1.30–8.53) (p = 0.034) greater risk of developing recurrent MI. Patients with severe coronary arteries atherosclerosis more frequently had eNOS T786C polymorphism of T/C genotype (OR = 4,67; 95 % CI: 1,38–15,37; p = 0,031). Conclusion. The eNOS T786C variants could be evaluated as recurrent MI risk factor in young and middle-aged patients.

RETRACTED: Relationship between common eNOS gene polymorphisms and predisposition to coronary artery disease: Evidence from a meta-analysis of 155 published association studies

BackgroundRelationship between endothelial nitric oxide synthase (eNOS) polymorphisms and predisposition to coronary artery disease (CAD) are still controversial and ambiguous. So we performed this meta-analysis to more precisely estimate relationship between eNOS polymorphisms and CAD by pooling the results of already published studies. MethodsWe searched Pubmed, Embase, Web of Science and CNKI for eligible studies. We used Review Manager to pool the results of eligible studies. ResultsOne hundred and fifty-five studies were included in this meta-analysis. We found that eNOS rs1799983, rs2070744 and rs869109213 polymorphisms were all significantly associated with CAD in the general population. We also detected similar significant results for eNOS rs1799983, rs2070744 and rs869109213 polymorphisms in both Caucasians and Asians in further subgroup analyses. ConclusionsThis meta-analysis demonstrated that eNOS rs1799983, rs2070744 and rs869109213 polymorphisms might influence predisposition to CAD in both Caucasians and Asians.

Role of Endothelial Nitric Oxide Synthase Polymorphisms in Atrial Fibrillation: A PRISMA-Compliant Meta-Analysis

BackgroundResearch interest in endothelial nitric oxide synthase(eNOS) polymorphisms and atrial fibrillation (AF) has grown in last recent years, but the results of individual studies are inconsistent due to their small sample sizes.Material/MethodsWe searched databases for eligible studies on eNOS and AF, extracted the relevant data, and rigorously screened them according to inclusion and exclusion criteria. Then, we evaluated the study quality according to the Newcastle-Ottawa scale score, and we pooled the odds ratios (ORs) and 95% confidence intervals (CIs) by using a random-effects model or fixed-effects model based on inter-study heterogeneity. In addition, we performed subgroup analysis and sensitivity analysis and assessed publication bias.ResultsAccording to the inclusion and exclusion criteria, we finally found 8 studies in this search. The recessive (OR=0.81; 95% CI=0.67 to 0.97; p=0.988; I2=0.0%) model showed that the eNOS 786T/C polymorphism was relevant to AF. We also found that the eNOS 786T/C polymorphism decreases the risk of AF, especially in white people (OR=0.81; 95% CI=0.67 to 0.97; P=0.023 for recessive model) and in the control population (OR=0.79; 95% CI=0.65 to 0.97; P=0.022 for recessive model). We found no obvious publication bias.ConclusionsThe eNOS gene loci 786T/C polymorphism is relevant to the risk of AF. Our results suggest that the 786T/C polymorphism significantly decreases AF risks in white people and control populations. Larger studies are required for further evaluation.

Impact of endothelial nitric oxide synthase polymorphisms on urothelial cell carcinoma development

ObjectivesUrothelial cell carcinoma (UCC), a major malignancy of the genitourinary tract, is induced through carcinogenic etiological factors. Endothelial nitric oxide synthase (eNOS) is one of the major isoforms of nitric oxide synthase and is involved in various pathophysiologic and physiologic processes. In this study, eNOS single-nucleotide polymorphisms were investigated to evaluate UCC susceptibility and clinicopathological characteristics. Materials and methodsTwo single-nucleotide polymorphisms of eNOS in 431 patients with UCC and 862 controls without cancer were analyzed using real-time polymerase chain reaction. ResultsThe results showed that 272 men with UCC having eNOS 894 G > T rs1799983 “GT + TT” variants had a high risk of developing a large tumor (T1–T4, P = 0.038). Furthermore, a correlation was observed between the expressions of eNOS and invasive tumor, metastasis and poor survival in urothelial carcinoma in The Cancer Genome Atlas data set. ConclusionOur results indicated that male patients with UCC carrying eNOS 894 G > T rs1799983 “GT + TT” genetic variants have a high risk of developing a large tumor, and eNOS polymorphisms may serve as a marker or therapeutic target in UCC treatment.

The Correlation of Endothelial Nitric Oxide Synthase (eNOS) Polymorphism and Other Risk Factors with Aneurysmal Subarachnoid Hemorrhage: A Case-Control Study.

Endothelial nitric oxide synthase gene (eNOS) polymorphism is an association with cerebral aneurysm formation, rupture, and vasospasm and plays a role in the a functional outcome. The aim of the study was to evaluate the role of eNOS gene polymorphism and further assess the predictors of outcome in the aneurysmal subarachnoid hemorrhage (aSAH). A prospective case-control study was conducted from 2009 to 2012 among those who presented with aSAH. A serum sample was collected from aSAH patients along with age and sex-matched healthy controls. The frequency of polymorphism of eNOS gene and other factors (demographic and aneurysmal) were correlated with functional outcome at six month of follow-up. 100 patients with aSAH and 100 healthy controls were enrolled in the cohort. The mean age of the patient group was 51.61 years and control group was 45.81 years with a male:female ratio of 1:1.38 and 1:1.08 for patients and controls, respectively. Among all eNOS polymorphisms, 4BB (65%) 24-VNTR, TT (71%) of T-786C, and GG (71%) of G947T were the most common and frequency was similar in the control group. The occurrences of hypertension, smoking, diabetes were 32%, 37%, and 7% respectively in the patient group. Maximum patients were in WFNS grade 1 (53%) followed by 23% grade 2 and only 10% in grade 4. Fisher grade 3 (57%) was the most common followed by Fisher grade 4 (28%). Most aneurysms (97%) were in anterior circulation. 83% of the aneurysms were clipped and 10% underwent coiling. Size-wise most of the aneurysms were in the middle group (6-9 mm) followed by bigger group (>10 mm) (37%); only 6% aneurysms were in the small aneurysm (<6 mm) group. 33% of the patients had evidence of vasospasm. TT of G894T polymorphism (60%) had the highest incidence of vasospasm. Univariate analysis showed smoking (OR: 3.19, CI: 1.19-8.84, P = 0.01), 4AA (OR: 12.15, CI: 1.13-624.9, P = 0.03) variety of 24-VNTR polymorphism, CC (OR: 15.39, CI: 1.60-762.8, P = 0.01) variety of T786C polymorphism, Fisher grade 4 (OR: 3.43, CI: 1.24-9.68, P = 0.01), WFNS grade (poor vs. good) (OR: 3.42, CI: 1.17-10.12, P = 0.02), vasospasm (OR: 3.84, CI: 1.42-10.75, P = 0.006), intraoperative rupture (OR: 4.77, CI: 1.55-15.27, P = 0.004) were significantly related with unfavorable outcome at 6 months follow-up. In regression analysis, smoking (CI: 0.06-0.69, P = 0.01), Fisher grade 4 (CI: 0.09-1.00, P = 0.05), and intraoperative rupture (CI: 0.05-0.89, P = 0.03) were correlated with an unfavorable outcome at 6 months follow-up. The eNOS gene polymorphism, smoking, clinical grade (WFNS), Fisher grade, intraoperative rupture, and vasospasm play a role in functional outcome after the treatment of cerebral aneurysms.

Effects of eNOS gene polymorphisms on individual susceptibility to cancer: A meta-analysis

BackgroundWhether endothelial nitric oxide synthase (eNOS) polymorphisms are implicated in cancer development remains controversial. Therefore, we performed this study to obtain a more conclusive result on associations between eNOS polymorphisms and cancer. MethodsLiterature retrieve was conducted in PubMed, Medline and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. ResultsForty-one studies were enrolled for analyses. Pooled overall analyses showed that rs1799983 (dominant model: p = 0.01; recessive model: p = 0.007; allele model: p = 0.005), rs2070744 (recessive model: p = 0.004) and rs869109213 (recessive model: p < 0.0001; allele model: p = 0.02) polymorphisms were all significantly associated with individual susceptibility to cancer. Further subgroup analyses revealed that rs2070744 and rs869109213 polymorphisms were only significantly associated with individual susceptibility to cancer in Caucasians, whereas the rs1799983 polymorphism was significantly associated with individual susceptibility to cancer in both Caucasians and Asians. ConclusionsOur findings indicated that rs1799983, rs2070744 and rs869109213 polymorphisms may serve as genetic biomarkers of cancer in certain ethnicities.

Associations between endothelial nitric oxide synthase gene polymorphisms and the risk of coronary artery disease: A systematic review and meta-analysis of 132 case-control studies.

The roles of endothelial nitric oxide synthase gene polymorphisms in coronary artery disease have been intensively analyzed, with inconsistent results. Therefore, we performed this study to better assess the relationship between endothelial nitric oxide synthase genetic variations and the risk of coronary artery disease. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios with 95% confidence intervals were used to evaluate associations between endothelial nitric oxide synthase polymorphisms and coronary artery disease. A total of 132 genetic association studies were finally included. Significant associations with the risk of coronary artery disease were detected for the rs891512, rs1799983, rs2070744, rs11771443 and rs869109213 polymorphisms. Further subgroup analyses according to ethnicity of participants revealed that the rs1799983 and rs2070744 polymorphisms were significantly associated with the risk of coronary artery disease in both Caucasians and Asians, whereas the rs869109213 polymorphism was only associated with the risk of coronary artery disease in Caucasians. When we stratified data based on type of disease, we found that the rs1799983, rs2070744 and rs869109213 polymorphisms were all significantly correlated with the risk of myocardial infarction or acute coronary syndrome in certain genetic models. In conclusion, our findings indicate that the rs891512, rs1799983, rs2070744, rs11771443 and rs869109213 polymorphisms may serve as genetic biomarkers of coronary artery disease.

Pharmacogenetic relevance of endothelial nitric oxide synthase polymorphisms and gene interactions.

Endothelial nitric oxide synthase (NOS3) is a key enzyme responsible for nitric oxide (NO) generation in the vascular endothelium. Endothelial dysfunction is characterized by reduced NO production, and is a hallmark of cardiovascular diseases. Drugs with cardiovascular action may activate NOS3 and result in NO release and vasodilation. Moreover, genetic variations affect NOS3 expression and activity, and may partially explain the variability in the responses to cardiovascular drugs. We reviewed NO signaling and genetic effects on NO formation, and the effects of NOS3 polymorphisms, haplotypes and gene-gene interactions within NO signaling pathways on the responses to cardiovascular drugs. We discuss the role of rare NOS3 variants and further gene-gene interactions analysis for the development of novel therapies for cardiovascular diseases.