eNOS Gene Polymorphisms Research Articles

Endothelial Nitric Oxide Synthase (eNOS) Glu298Asp Gene Polymorphism (G894T) as a Risk Factor for Type 2 Diabetes Mellitus in the Tunisian Population

Introduction: Diabetes mellitus is a chronic disease whose global expansion gives it the characteristics of a pandemic. Diabetes risk factors are well known. In this work we proposed to study the role of genetic polymorphism of the eNOS G894T gene in the development of diabetes on the one hand and of these degenerative complications other. Methods: We conducted a prospective case-control study in which we included 200 subjects divided into 100 patients with type 2 diabetes and 100 controls in apparent good health. For each patient and control we measured lipid parameters, CRP-us and sought the G894T polymorphism of eNOS gene by PCR-RFLP. Results: The analysis of our results shows a statistically significant elevated TG values (p < 10﹣3), Lp (a) (p < 10﹣3), and CRP-us (p < 10﹣3) in type 2 diabetes compared with controls. The mutated genotypes of GT eNOS gene was significantly more frequent in diabetic patients. In our series, we did not notice any significant difference in genotype or allele frequency between diabetics with and without degenerative complications. Conclusion: The G894T polymorphism of eNOS gene appears to be a risk factor of T2DM. His role in the development of degenerative complications remains proved.

Role of and genes polymorphisms in the pathogenesis of stroke of the Erzya population in the Republic of Mordovia

To determine the frequency of GPIIIa and eNOS genes polymorphisms in patients with ischemic stroke in the Erzya population in the Republic of Mordovia. An open, prospective, randomized study included 4 groups: 1) Erzya with ischemic stroke (main group, n=65), 2) Russians with ischemic stroke (comparison group, n=60), 3) Erzya healthy volunteers (control-1, n=63), 4) Russian healthy volunteers (control-2, n=61). T1565C polymorphism of GPIIIa gene (rs5918) and G894T polymorphism of eNOS gene (rs1799983) were determined by real-time PCR. In the population of healthy Erzya, the accumulation of mutant alleles of the GPIIIa gene was observed with less frequency than in healthy Russians, however, in the absence of differences in the frequency of homozygous carriage of both mutant and normal alleles, in the Erzya, the accumulation of the mutant allele in heterozygous genotypes prevailed. In patients with stroke, the probability of detecting the allele C of the GPIIIa gene in the Erzya was significantly higher than in the Russians, as was the likelihood of heterozygous carriage of the C/T genotype. No differences between eNOS allele frequencies were found between the groups of healthy Erzya and Russian volunteers. The higher frequency of the mutant allele T was found in Russian patients with stroke while the heterozygous carriage of the G/T genotype, which had an unfavorable prognostic value, predominated in the Erzya.

THE ROLE OF VARIABILITY OF CANDIDATE GENES eNOS, MnSOD2, ADRB1 IN THE DEVELOPMENT OF CARDIOVASCULAR PATHOLOGY IN NEWBORN

The study of gene polymorphism has been carried out to inform health care practitioners on genetic studies that can be used in clinical practice, and the genes under investigations aim at finding early manifestations of cardiovascular disorders. The possibility of determining the ways of correction of the detected cardiovascular pathology necessitates the prospect of further research starting from the neonatal period. To study the frequency of occurrence of genotypes of endothelial nitric oxide (eNOS) gene candidates polymorphism, mitochondrial superoxide dismutase (MnSOD2) 1 mutation and β1-adrenoreceptor (ADRB1) gene polymorphism in neonatal infants from perinatal risk groups the study involved examination of 186 newborns: 102 healthy full-term newborns, 25 newborns after asphyxia, 46 premature newborns and 13 newborns with intrauterine growth retardation. The study showed that the frequency of distribution of endothelial nitric oxide synthase (eNOS) C786T genotypes, mitochondrial superoxide dismutase (MnSOD2) T49C and β1-adrenergic receptor (ADRB1) Ser49Gly in newborns from perinatal risk groups in the neonatal period did not differ from healthy neonates.The CT genotype (p<0.05) of the endothelial nitric oxide synthase (eNOS) gene polymorphism C786T can be considered one of the predictors of cardiovascular development in newborns, which requires further clinical and instrumental comparison. Information on the prevalence of polymorphisms of genes associated with the development of cardiovascular events should be considered when developing a set of individual preventive measures.

Диагностически значимые факторы-предикторы рестенозирования в стенте у пациентов с ИБС

В последние годы все больше внимания уделяется интервенционным способам лечения ИБС. Однако, несмотря на многочисленные клинические исследования остается нерешенным вопрос рестенозирования стентов после интервенционных вмешательств. На сегодняшний день становится актуальным изучение молекулярных механизмов рестенозирования коронарных артерий, а также поиск новых генетически обусловленных предикторов развития рестеноза после стентирования. Воздействие NO-синтаз на развитие дисфункции эндотелия не вызывает сомнения, в то же время исследования, посвященные изучению влияния полиморфизма генов NOS на вероятность рестенозирования в стенте единичны и основаны на небольшом количестве клинических наблюдений. Вышесказанное свидетельствует об актуальности данного исследования, результаты которого сформировали новые представления о роли генов NO-синтаз в формировании предрасположенности к гиперпролиферации стентов у больных с ИБС. Цель работы - выделение диагностически значимых факторов-предикторов рестеноза после стентирования коронарных артерий у паицентов с ИБС и определение их чувствительности и специфичности при помощи ROC-кривых. Методика: в основу данного исследования положены результаты целенаправленного обследования 484 пациентов с верифицированным диагнозом ИБС, находившихся на лечении в отделении атеросклероза и хронической ишемической болезни сердца ФГБНУ «Научно-исследовательский институт кардиологии» СО РАН. Стентирование коронарных артерий было проведено у 210 чел. - группа рестеноза (n = 60) и группа без рестеноза (n = 150). Исследование генотипа проводили путем выделения геномной ДНК из цельной венозной крови обследуемых по стандартной неэнзиматической методике, а также исследования полиморфизмов генов NOS методом полимеразной цепной реакции (ПЦР). Результаты. Установлено 6 предикторов развития рестенозирования после стентирования при ИБС: протяженность стеноза, сужение коронарной артерии (% стеноза), полиморфизм 894G/T, наличие в анамнезе АГ, наличие у больного гаплотипов TCabGT11 и TTabGG11, определена их чувствительность и специфичность при помощи ROC-кривых. Установлено, что в Сибирской популяции у носителей гаплотипа TCabGT11 наиболее вероятно развитие рестенозирования в стенте, а при наличии гаплотипа TTabGG11 риск рестенозирования минимален. Заключение. Полиморфизмы 894 G/T гена eNOS ассоциированы с риском развития рестеноза, что может быть использовано как дополнительные маркеры риска развития рестеноза после стентирования коронарных артерий. In recent years, growing attention has been paid to interventional treatment of ischemic heart disease (IHD). However, despite numerous clinical studies, the issue of in-stent restenosis following interventions remains unsolved. At present, studying molecular mechanisms of coronary restenosis along with searching for new, genetically determined predictors of in-stent restenosis has become relevant. Effects of NO synthases on development of endothelial dysfunction are above any doubt; however, studies focusing on the effect of NOS gene polymorphism on probability of in-stent restenosis are scarce and based on a small number of clinical observations. Therefore, the present study is highly relevant as it has resulted in development of new concepts on the role of NO-synthase genes in predisposition to in-stent hyperproliferation in patients with IHD. The aim of this study was to identify diagnostically significant, predictive factors for in-stent coronary restenosis in patients with ischemic heart disease and to determine their sensitivity and specificity using ROC curves. Methods. This study was based on data from a targeted evaluation of 484 patients with a verified diagnosis of IHD who were managed at the Department of Atherosclerosis and Chronic Ischemic Heart Disease of the Research Institute of Cardiology, Siberian Branch of the Russian Academy of Medical Sciences. Coronary artery stenting was performed for 210 patients divided into two groups, with restenosis (n = 60) and without restenosis (n = 150). The genotype was studied on isolated genomic DNA from whole venous blood using a standard non-enzymatic technique, as well as by studying NOS gene polymorphisms using the polymerase chain reaction (PCR). Results. Six predictors for in-stent restenosis in IHD were identified - stenosis length, per cent narrowing of the coronary artery (% stenosis), 894G/T polymorphism, history of arterial hypertension, presence of TCabGT11 and TTabGG11 haplotypes, and their sensitivity and specificity determined with ROC curves. In the Siberian population, development of in-stent restenosis most likely occurred in carriers of the TCabGT11 haplotype while the risk for restenosis was minimal in the presence of the TTabGG11 haplotype. Сonclusion. The 894 G/T eNOS gene polymorphisms are associated with a risk for restenosis and might be used as additional markers for the risk of restenosis following coronary stenting.

Endothelial nitric oxide synthase genepolymorphisms in patients with slowcoronary flow.

Background and aimsThe aim of this study was to explore potential associations of the intron 4 variable number of tandem repeats (VNTR) and E298A polymorphisms of the endothelial nitric oxide synthase (eNOS) gene with slow coronary flow (SCF). The association between plasma nitrate and nitrite (NOx) concentrations and eNOS gene polymorphisms was also assessed.Materials and methodsThe intron 4 VNTR and E298A polymorphisms of the eNOS gene were evaluated in the isolated DNA blood samples obtained from the SCF patient group (n = 30) and healthy group consisted of age- and sex-matched controls (n = 61).ResultsPlasma NOx level was significantly lower in patients with SCF than in controls. In addition, patients with SCF have significantly lower nitric oxide levels than control subjects within each genotype variants. The allele and genotyped frequencies of the eNOS intron 4 VNTR and E298A polymorphisms were similar between patients with SCF and the controls. Plasma NOx concentrations with respect to the relevant genotypes were found insignificant.Discussion and conclusionPlasma NOx is lower in patients with SCF than in healthy subjects. Our findings may suggest the lack of association between intron 4 VNTR and E298A polymorphisms of the eNOS gene and SCF.

Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects

Congenital heart defects are structural cardiovascular malformations that arise from abnormal formation of the heart or major blood vessels during the fetal period. To investigate the association of 4 single nucleotide polymorphisms (SNPs) in the MTHFD1, eNOS, CBS and ACE genes, we evaluated their relationship with CHD in Iranian patients. In this case–control study, a total of 102 children with CHD and 98 control children were enrolled. Four SNPs including MTHFD1 G1958A, eNOS G894T, CBS C-4673G and ACE A2350G were genotyped by PCR-SSCP, Multiplex ARMS PCR and PCR-RFLP methods and confirmed by direct sequencing. We genotyped 102 patients and 98 controls for four polymorphisms by statistically analysis. There were three SNPs including MTHFD1 G1958A, eNOS G894T and ACE A2350G which might increase the risk of CHD, but CBS C-4673G was not significantly different between patients and controls. (P = 0.017, P = 0.048, P = 0.025 and P = 0.081 respectively). The allele frequencies of three SNPs for MTHFD1 G1958A, eNOS G894T and ACE A2350G in CHD are higher than that in control. Our results show that there is a significant relationship between MTHFD1 G1958A, eNOS G894T and ACE A2350G polymorphisms with CHD. Therefore, The AA and GA genotypes of MTHFD1 G1958A, TT and GT genotypes of eNOS G894T and the AA and GA genotypes of ACE A2350G are susceptible factors for CHD and may increase the risk of CHD.

The Endothelial Nitric Oxide Synthase (NOS3-786T>C) Genetic Polymorphism in Chronic Heart Failure: Effects of Mutant -786C allele on Long-term Mortality.

Nitric oxide plays an important role in the regulation of basal vascular tone and cardiac myocyte function. We investigated the NOS3-786T>C polymorphism in chronic heart failure (CHF) and its effects on long-term mortality. Ninety-one patients with CHF who were referred to the Department of Cardiology of Siyami Ersek Cardiovascular and Thoracic Surgery Center for cardiopulmonary exercise testing between April 2001 and January 2004 and 30 controls were enrolled in this study. Patient were followed prospectively for a period of 1 to 12 years. Patients and controls were divided into three groups: TT, TC and CC, according to their NOS3-786T>C polymorphism. We noted that there was no significant difference in the genotype distribution between patients and controls. There was also no significant difference in endothelial nitric oxide synthase (eNOS) gene polymorphism between ischemic HF and nonischemic HF. During the follow-up period, 61 (67%) deaths occurred. The nonsurvivor group had lower left ventricular ejection fraction (LVEF) (p = 0.01), reduced peak oxygen consumption (p = 0.04) and were of older age (p = 0.001). Age, LVEF, peak oxygen consumption and genotype were found to be predictors of mortality (p < 0.05). Additionally, mortality was significantly increased in -786CC genotype patients compared to TT genotype patients (hazard ratio = 2.2; p = 0.03). By multivariate analysis, age and eNOS genotype were determined to be significant independent predictors of death. Additionally, Kaplan-Meier analysis confirmed that homozygote -786C genotype was associated with an increased risk of death (χ2 = 4.6, p = 0.03). Our findings showed that the NOS3-786T>C polymorphism was associated with an increased risk of mortality in patients with CHF.

ASSOCIATION OF ENOS GENE POLYMORPHISMS AS A RISK FACTOR OF CORONARY IN-STENT RESTENOSIS

Background: In recent years more attention is paid to the methods of interventional treatment of coronary artery disease. However, despite the numerous clinical studies the problem of stent restenosis after interventional procedures remains an important one. The studies of the molecular mechanisms of restenosis of coronary arteries and findings for new genetically determined predictors of restenosis after stenting become vital and essential. The NO-synthase influence on the development of endothelial dysfunction is practically assured, but the studies on the NOS genes' polymorphism effect on the incidence rate of in-stent restenosis are isolated and based on a limited number of clinical observations. The determined facts demonstrate the relevance of the conducted study, the results of which formed a new understanding of the role of NO-synthase genes in the predisposition to hyper-proliferative stents in patients with coronary artery disease. Aims: Set association between the eNOS gene polymorphisms and the risk of restenosis in patients with coronary artery disease hospitalized for coronary restenosis.Materials and methods: We examined 484 patients with the verified diagnosis of the ischemic heart disease who underwent treatment at the unit of atherosclerosis and chronic coronary heart disease of «Cardiology Research Institute». Stenting of coronary arteries was performed in 210 people. The group of a restenosis enrolled 60 patients and the group without restenosis — 150. Genotyping was performed by non-enzymatic technique for isolation of genomic DNA from the venous blood of the surveyed, NOS genes' polymorphisms were detected by polymerase chain reaction (PCR). Results: The established development of in-stent restenosis was associated with the following eNOS gene polymorphisms: VNTR ― in homozygotes for the minor allele (genotype aa) and heterozygotes (genotype ab); 894G/T ― in heterozygotes (the GT genotype) and homozygotes (TT genotype).Conclusions: VNTR and 894G/T polymorphisms of eNOS gene are associated with risk for restenosis and can serve as additional markers for risk of restenosis after coronary stenting.

Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke.

Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09–2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16–2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06–2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan.

Abstract P271: Association Between Nitric Oxide Synthase Gene Polymorphism ( Glu298Asp ) and Blood Pressure in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Endothelial NO synthase ( eNOS ) gene polymorphism at position 894 (G&gt;T, Glu298Asp ) resulting in a T allele is related to higher blood pressure (BP) levels, but the association of Glu298Asp and temporal increase in BP in adulthood has not been studied, nor is it known whether the association between Glu298Asp and BP is modified by habitual intake of fruits and vegetables, an abundant source of nitrate for conversion to NO. Hypothesis: We hypothesized that homozygous (TT) or heterozygous genotype (GT) status of Glu298Asp is associated with BP increase over a course of 9 years among black and white adults, compared to normal genotype (GG). Further, the association is amplified by higher habitual intake of fruits and vegetables. Methods: Among 9488 white (mean age: 54.3 years, 47.0% men) and 2861 black members of the ARIC cohort (mean age: 53.4 years, 37.2% men) at baseline (1987-1989), genotyping of the NOS3 Glu298Asp polymorphism (rs1799983) was conducted using the TaqMan assay (Applied Biosystems, Foster City, CA, USA). The rs1799983 levels 1.5-2, 0.5-1.49, &lt;0.5 were categorized as TT, GT, GG, respectively. We used the average of repeated sitting blood pressure at 4 cohort examinations through 1996-1998. Average intake of vegetables and fruit was calculated from food frequency questionnaires at exams 1 and 3, and analyzed as quartiles. A diet score without fruit and vegetables intake was created using principal component analysis. Mixed models were used to estimate the association between NOS3 G894T (TT or GT vs. GG) with level and change of SBP and DBP, adjusting for age, sex, genotypes, BMI, smoking status, diabetes, and physical activity. The analysis was also conducted within each quartile of vegetables and fruit intake, with further adjustment for the diet score without fruit and vegetables intake. Results: The genotypes of TT, GT and GG of Glu298Asp were present in 800 (8.4%), 4057 (42.8%), 4631 (48.8%) white participants, and 26 (0.9%), 510 (17.8%), 2335 (81.3%) black participants. Among whites with the genotype GT/TT, DBP increased 2.46 mmHg (95% CI: 0.02, 4.90) over 9 years compared to GG participants. The interaction between Glu298Asp and intake of fruit and vegetables was not statistically significant. There was no statistically significant association between GT/TT and SBP, nor with 9-year change of SBP or DBP among black participants. Conclusion: Carrier status of the GT/TT genotypes of Glu298Asp is associated with higher level of DBP among white adults, but not with SBP over a course of 9 years compared to the GG genotype of Glu298Asp . There is no interaction found between Glu298Asp and intake of fruit and vegetables in association with SBP or DBP.

The Endothelial Nitric Oxide Synthase Gene T-786C Polymorphism Increases Myocardial Infarction Risk: A Meta-Analysis.

BackgroundPolymorphisms of the endothelial nitric oxide synthase (eNOS) gene are reportedly associated with myocardial infarction (MI) risk. However, definitive evidence of this association is lacking. In this study, we investigated the potential association of eNOS gene polymorphisms with MI risk by conducting a meta-analysis of studies evaluating this association.Material/MethodsPubMed, Web of Knowledge, ScienceDirect, China National Knowledge Infrastructure (CNKI), WanFang, and Database of Chinese Scientific and Technical Periodicals (VIP) were searched for relevant studies. Pooled odds ratios (OR) with 95% confidence interval (CI) were calculated to evaluate the association of eNOS gene T-786C and 4b4a polymorphisms with MI risk.ResultsFifteen studies with 8,067 controls and 4,923 MI cases were included in the final meta-analysis. In the overall analysis, T-786C (rs2070744) polymorphism was associated with MI risk (p<0.05, OR=1.69, 95% CI: 1.53–1.86 for T vs. C; p<0.05, OR=2.76, 95% CI: 2.03–3.75 for TT vs. CC; p<0.05, OR=1.74, 95% CI 1.56–1.95 for TT vs. (CT + CC); p<0.05, OR=2.43, 95% CI: 1.79–3.30 for (CT + TT) vs. CC). In addition, a significant association between 4b4a VNTR polymorphism and MI risk was observed. On sub-group analyses by ethnicity, a significant increase in MI risk was observed separately for Asian and Caucasian populations for T-786C polymorphism, but not for the 4b4a polymorphism.ConclusionsIn this meta-analysis, T-786C polymorphism of the eNOS gene was associated with the risk of MI, especially in the Asian populations.

Sickle cell anemia - Nitric oxide related genetic modifiers of hematological and biochemical parameters.

Sickle cell anemia (SCA) is an inherited blood disorder. SCA patients present clinical and hematologic variability that cannot be only explained by the single mutation in the beta-globin gene. Others genetic modifiers and environmental effects are important for the clinical phenotype. SCA patients present arginine deficiency that contributes to a lower nitric oxide (NO) bioactivity. The aim of this work is to determine the association between hematological and biochemical parameters and genetic variants from eNOS gene, in pediatric SCA patients. 26 pediatric SCA patients were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques in three important eNOS gene polymorphisms - rs2070744, rs1799983 and intron 4 VNTR. Results from this study show a significant statistical association between some parameters and genetic variants: an increased reticulocyte count and high serum lactate dehydrogenase levels were associated with both the rs2070744_TT and the rs1799983_GG genotypes at eNOS gene and high levels of neutrophils were associated with the eNOS4a allele at intron 4 VNTR. Our results reinforce the importance of NO bioactivity in SCA. We presume that NO, and its precursors might be used as therapy to improve the quality of life of SCA patients.

Heterozygous eNOS Deficient Mice as a Model to Examine the Effects of eNOS Haploinsufficiency on the Cerebral Circulation

Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature. A major mechanism associated with the impairment of endothelial function with eNOS deficiency and a high fat diet appears to be related to increases in plasma IL-6 that serves to further reduce the bioavailability of NO either directly or indirectly via reductions in eNOS expression or activity and via increases in vascular superoxide. Taken together, these findings provide important insights into genetic and molecular mechanisms that promote endothelial dysfunction in response to a high fat diet in cerebral blood vessels with inherent reductions in eNOS gene expression, such as those due to eNOS gene polymorphisms. These findings also highlight the importance of eNOS+/- mice to study the effects of eNOS haploinsufficiency on cerebral blood vessels.

Association between endothelial nitric oxide synthase gene polymorphisms and risk of ischemic stroke: A meta-analysis.

Previously published studies that have examined whether the three polymorphisms, G894T, T786C, and 4b/a in the endothelial nitric oxide synthase (eNOS) gene, are associated with ischemic stroke (IS) have reported conflicting results. Thus, we performed a meta-analysis to examine the potential association between these three single nucleotide polymorphisms (SNPs) of the eNOS gene and IS risk. A literature search was carried out for eligible candidate gene studies published before August 05, 2015 in the PubMed, Embase, and Google Scholar databases. The following combinations of main keywords were used in our study: ('endothelial nitric oxide synthase') or ('eNOS') and ('G894T, 4b/a, and T786C') and ('polymorphism') or ('polymorphisms') and ('Ischemic Stroke' or 'IS') and ('Cerebral Infarction' or 'CI') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using fixed or random effects model. Meta-regression analysis was used to investigate the potential sources of heterogeneity. Begg's funnel plots were used to explore the publication bias, and heterogeneity was assessed by I2 test. Twenty seven case-control studies involving 6733 cases and 7305 controls were analyzed in our meta-analysis. Significant association was observed for G894T (OR = 1.17; 95% CI: 1.08 to 1.28; P< 0.001) and 4b/a (OR = 1.25; 95% CI: 1.13 to 1.39; P < 0.001) whereas a non-significant association was observed for T786C (OR = 1.11; 95% CI: 0.98 to 1.26; P =0.109) eNOS gene polymorphisms and IS. Our meta-analysis establishes that the G894T and 4b/a polymorphisms of eNOS gene are significantly associated with the risk of IS. However, a non-significant association was found between T786C polymorphism of the eNOS gene and IS risk. Further prospective large epidemiological studies need to be done to confirm these findings.

Atherosclerosis: analysis of the eNOS (T786C) gene polymorphism.

The coronary arteriosclerotic disease is the most common cardiovascular disease. Atherosclerosis affects large- and medium-sized arteries leading to severe thrombosis or artery stenosis that could evolve to myocardial infarction, ischemic stroke, ischemic injury of kidneys and intestines, and several other life-threatening clinical manifestations. Nitric oxide has been shown to be a promising therapeutic agent against cardiovascular diseases. The eNOS gene assumes several important functions, including regulation of vascular tone and regional blood flow, the suppression of vascular smooth muscle cell proliferation, and modulation of leukocyte-endothelium interactions. The T786C polymorphism is an important point mutation, where thymine is changed to cytosine. T786C significantly reduces the activity of the eNOS promoter gene. Two hundred and ninety-seven peripheral blood samples were collected from patients with the previous diagnosis of atherosclerotic disease based on clinical examination and confirmed by imaging methods. Results were compared using the chi-square test and the G-test. In the present study, the TC genotype was more frequent in both case and control groups with no statistically significant difference. Comparing the relation TC/TT and CC genotypes in the case and control groups, there was no statistically significant difference. No significant difference was found when genotypes were analyzed regarding gender and smoking. Our results suggest a strong tendency of the T allele, in single or double dose, to be associated with atherosclerosis that was not confirmed by the scientific data.

Endothelial nitric oxide synthase gene polymorphisms are associated with cardiovascular risks in prehypertensives

Though endothelial nitric oxide synthase (eNOS) gene polymorphism is documented in the causation of hypertension, its role in prehypertension has not been investigated. The present study was conducted in 172 subjects divided into prehypertensives (n = 57) and normotensives (n = 115). Cardiovascular (CV) parameters including baroreflex sensitivity (BRS) by continuous BP variability assessment and sympathovagal imbalance (SVI) by heart rate variability analysis were recorded. Biochemical parameters for insulin resistance (homeostatic model for assessment of insulin resistance), oxidative stress, lipid risk factors, renin, and inflammatory parameters were measured. Genotyping for eNOS polymorphisms rs1799983 (298G>T) and rs2070744 (-786T>C) was performed by polymerase chain reaction-restriction fragment length polymorphism method. Multiple regression analysis was done to assess the association between SVI and metabolic markers, and multivariate logistic regression was done to determine the prediction of prehypertension status by genotype, BRS, and ratio of low-frequency to high-frequency in these subjects. The BP variability, heart rate variability, and biochemical parameters were significantly altered in prehypertensives. The eNOS polymorphisms were found to be associated with prehypertension. BRS, the marker of SVI, was significantly associated with BP, homeostatic model for assessment of insulin resistance, and tumor necrosis factor alpha in 298GG genotype of prehypertensive population. The eNOS gene polymorphisms appear to be associated with prehypertension. 298G>T and -786T>C contribute to SVI in young prehypertensives attributed by insulin resistance and inflammation. The CV risks were associated with prehypertension status in prehypertensives expressing both 298GG and -786TT genotypes. Association of CV risks with SVI appears to be stronger in prehypertensives expressing GG genotype.

Association of eNOS and ACE gene polymorphisms and plasma nitric oxide with risk of non-small cell lung cancer in South India.

The role of ACE and eNOS gene polymorphisms and their association with various cancers were reported. However, their role in the lung cancer is unclear. In this study, we analyzed eNOS and ACE gene polymorphisms and the risk of non-small cell lung cancer (NSCLC) in South Indian population. For the eNOS gene, the homozygous "AA" genotypic frequency was significantly associated with NSCLC with an overall risk of 3.6-fold (P=0.006, odds ratio=3.58, 95% confidence interval=1.66, 7.723). The heterozygous "I/D" genotypic frequency of ACE gene was significantly higher in NSCLC patients when compared to the controls with a 2.29-fold risk for NSCLC. Multiple regression analyses indicated that gender, smoking status, and polymorphisms in eNOS and ACE genes as the strongest predicting factors for an increased susceptibility to NSCLC. We report for the first time that polymorphisms in the eNOS "A/A" (homozygous mutant) and ACE "I/D" genotypes might contribute to the increased risk of NSCLC in the South Indian population.

Interactive role of endothelial nitric oxide synthase gene polymorphisms in T2D with CAD and CAD patients of Punjab (North-West India)

Dysregulation of endothelial nitric oxide synthase (eNOS) activity causes the reduction in the production of nitric oxide (NO) which is an early indicator of type 2 diabetes (T2D) and cardiovascular complications. The present study evaluates the association of −786 T > C, 894 G > T, and 4a/b polymorphisms of eNOS gene in total of 1223 individuals enrolling 307 coronary artery disease (CAD) cases, 486 T2D cases with (n = 170) and without (n = 316) CAD as the secondary macrovascular complication, and 430 healthy controls from Punjab (North-West India). Genotyping of −786 T > C and 894 G > T polymorphisms was done with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the genotyping of 4a/b insertion/deletion polymorphism was done by PCR. The minor allele frequency (MAF) of −786 T > C polymorphism was higher in CAD (21.8 %), T2D + CAD (22.4 %), and T2D cases (18.4 %) as compared to healthy controls (17.6 %). However, in single-locus analysis, no significant results were obtained for eNOS polymorphisms in any of the studied groups. Significant association of C-b-G haplotype with the risk of both CAD [P = 0.003, odds ratio (OR) = 1.89 (1.04–3.45)] and T2D [P = 0.019, OR = 1.69 (0.92–3.13)] was observed. Diplotype analysis showed that TbG/CbG haplotype combination conferred risk towards CAD and T2D [P = 0.01, OR = 2.04 (1.18–3.57); P = 0.006, OR = 2.13 (1.22–3.57), respectively]. Furthermore, phenotypic parameters like waist circumference, high-density lipoprotein, and waist to height ratio are significantly associated with 894 G > T genotypes among CAD patients. In conclusion, the eNOS polymorphisms did not provide any conclusive result individually; however, their interactive effect gives some insights towards eNOS role in the population of Punjab.

Гостре ураження нирок у доношених новонароджених після асфіксії та роль поліморфізму АСЕ, AGT2R1, eNOS генів у його розвитку

Background. Acute kidney injury (AKI) is a fairly common pathology among newborns who had asphyxia at birth. Objective. To analyze the incidence of AKI in neonates with asphyxia, and study the impact of functional polymorphisms of genes ACE, AGT2R1, eNOS in its development. Methods. A prospective cohort study was conducted, which included 72 newborns with Apgar scores at birth <6 points. The criterion for determining AKI became creatinine level above 130 mg/dL after 48 hours of life. In these cohorts of infants I/D polymorphism of ACE gene, A/C polymorphism of AGT2R1gene and a/b polymorphism of eNOS gene were defined. Statistical processing of the results took place using simple and multiple logistic regression analysis. Results. In 20 (27.8%) of newborns with asphyxia creatinine level was above 130 mg/dL, only 6.94% of the infants had oliguria. With the development of AKI at multiple logistic regression analysis AA genotype of AGT2R1 gene (OR 0.21), Apgar score at 5 minutes of life (0.30) and meсonium aspiration (OR 6.02) were significantly associated. Conclusions. AA genotype of AGT2R1 gene significantly reduces the chances of the child with asphyxia to have acute kidney injury. Key words: neonates, asphyxia, acute kidney injury, ACE, AGT2R1, eNOS, gene polymorphism.

Endothelial nitric oxide synthase gene polymorphisms and the risk of vasculopathy in sickle cell disease

Background: Sickle cell disease (SCD) is one of the major health problems in many parts of the world. SCD is characterized by multisystem complications with marked variability in its severity between patients, probably linked to nitric oxide (NO). Endothelial nitric oxide synthase (eNOS) enzyme which is responsible for NO synthesis may be implicated in SCD pathophysiology.Aim of the study: To explore the possible association between the eNOS gene polymorphisms and severity of SCD. Furthermore, we examined the genomic diversity of these polymorphisms in SCD patients.Methods: We genotyped 100 SCD patients and 80 controls were genotyped for eNOS 4a/b and eNOS 786T>C polymorphisms, using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism assay, respectively. Polymorphisms were analyzed in relation to severity of SCD manifestations.Results: The homozygous mutant eNOS-786T>T genotype was significantly associated with high risk of acute chest syndrome (ACS). The wild-type eNOS-4a/4b genotype was protective against vaso-occlusive crisis (VOC) and pulmonary hypertension (PHTN). The mutant homozygous haplotype (C –4a) was significantly associated with the risk of ACS, VOC, and PHTN.Conclusion: eNOS intron 4 and eNOS T>C gene polymorphisms may be used as a genetic marker of prognostic value in SCD, as they are associated with unfavorable clinical outcomes.