A meta-analysis of eNOS and ACE gene polymorphisms and risk of pre-eclampsia in women

A meta-analyses of endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) gene polymorphisms in pre-eclampsia was performed. We shortlisted 33 studies (17 for ACE; 16 for eNOS gene polymorphisms), of which 29 articles (16 for ACE and 15 for eNOS) were analysed. Overall, 1,620 cases with pre-eclampsia and 2,158 controls were analysed for intron 16 insertion-deletion polymorphism in ACE gene. A total of 1,610 subjects with pre-eclampsia and 2,875 controls were analysed for the Glu298Asp in eNOS gene. Overall, the random-effects odds ratio (OR) with Glu298Asp in eNOS gene was 0.958 (95% confidence intervals, CI 0.747-1.228, p > 0.05), and for the insertion-deletion/ACE polymorphism was 0.987 (95% CI 0.698-1.395, p > 0.05). Significant heterogeneity was observed in the studies that evaluated polymorphisms in ACE (Q value = 55.6; I(2) = 73; p value = 0.000); and eNOS (Q value = 37.2; I(2) = 62.4; p value = 0.001) polymorphisms. No significant risk of pre-eclampsia was observed in both eNOS and ACE genes with these polymorphisms.     

Endothelial nitric oxide synthase polymorphism is not associated with placental abruption in Finnish women

OBJECTIVE: To study whether genetic variability in the gene encoding endothelial nitric oxide synthase (eNOS) affects individual susceptibility to the development of placental abruption during pregnancy. METHODS: One hundred and sixteen pregnant women with placental abruption and 113 healthy controls were genotyped for Glu298Asp polymorphism in the eNOS gene. Chi-square analysis was used to assess the differences in genotype and allele frequencies between the two groups. RESULTS: A statistically similar allelic distribution of eNOS Glu298Asp polymorphism was observed in the two groups, with the frequency of the variant G allele being 66.8% in the abruption group and 68.1% in the control group (OR 0.94, 95% CI: 0.64-1.39; p = 0.76). The genotype distribution of the eNOS polymorphism was also found to be statistically similar (p = 0.72). CONCLUSIONS: The observed genotype data in subjects from eastern Finland suggest that the Glu298Asp polymorphism of the eNOS gene does not contribute to placental abruption in this population.     

Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer

OBJECTIVE: Nitric oxide (NO) is involved in angiogenesis and tumor growth. We attempted to establish an association between two polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and vulvar cancer. METHODS: We used peripheral venous blood sampling, DNA extraction, and polymerase chain reaction (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7 Glu298Asp polymorphisms. RESULTS: The presence of a polymorphic NOS3*A allele (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6-2.0; P = 0.9) or a polymorphic NOS3 exon 7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3-1.0; P = 0.09) was not associated with vulvar cancer. Within the vulvar cancer group, the presence of a polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not associated with clinico-pathological parameters such as advanced tumor stage, groin lymph node involvement, tumor grading, and age at diagnosis. Survival analysis demonstrated that the presence of a polymorphic NOS3*A allele was associated with a significantly reduced disease-free survival time (P = 0.03), whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not associated with disease-free survival (P = 0.5). CONCLUSIONS: We are the first to report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation within intron 4, but not ithin exon 7 of NOS3, influences the length of disease-free survival, but not the biological phenotype of vulvar cancer.     

Endothelial nitric oxide synthase polymorphism in preeclampsia

OBJECTIVE: We wished to determine whether genetic variability in the gene encoding endothelial nitric oxide synthase (eNOS) modifies individual susceptibility to the development of preeclampsia. METHODS: The study involved 132 preeclamptic and 113 healthy control pregnant women who were genotyped for the Glu298Asp polymorphism in the eNOS gene. Chi(2) analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. RESULTS: A statistically similar allelic distribution of eNOS Glu298Asp polymorphism was observed in the two groups, with the frequency of the variant G allele being 74.6% in the preeclampsia group and 67.7% in the control group (P = .091; odds ratio 1.40, 95% confidence interval 0.95, 2.01). Accordingly, the genotype distribution of the NOS polymorphism in the preeclamptic and control groups was found to be similar (P = .233). CONCLUSION: These genotype data in subjects from eastern Finland were not suggestive of an important contribution of the Glu298Asp polymorphism in the NOS gene on preeclampsia across populations. However, the observed association between the G allele and disease risk, of borderline significance, may imply that other polymorphism(s) in the gene may modify disease risk.     

Vascular endothelial growth factor gene polymorphisms in North Indian patients with recurrent miscarriages

The association of four common polymorphisms of vascular endothelial growth factors (VEGF) with recurrent miscarriages(RM) was evaluated in North Indian women for 200 patients with RM and 200 controls. The subjects were genotyped for the polymorphisms 2578C/A, 2549 18-bp I/D, 1154G/A and +936C/T. Association of VEGF genotypes, alleles and haplotypes with recurrent miscarriage were evaluated by Fisher’s exact test. 1154G/A and +936C/T modified the risk of RM. The 1154A allel and +936T allel significantly increased the risk of RM (OR = 1.485, P = 0.0210, 95% CI 1.072–2.057 and OR = 1.869, P = 0.0054, 95% CI 1.214–2.876 respectively). Risk was further increased when –1154A/A genotype and +936C/T genotype were considered (OR = 2.0, P = 0.0310,95% CI 1.068–3.747 and OR = 1.716, P = 0.0293, 95% CI 1.058–2.784 respectively). However, no association was found between 2578C/A or 2549 18-bp I/D and RM. Four haplotypes, AIAC, ADAC, CIAT and ADGT, were found to predispose to RM while the haplotypes CIAC, CDGT and ADGC were found to show protective effect. In conclusion, two common polymorphisms of the VEGF gene,1154G/A and +936C/T, increase the risk of RM in North Indian women. RM is also predisposed in the presence of haplotypes AIAC,ADAC, CIAT and ADGT.     

Endothelial nitric oxide synthase gene polymorphisms in recurrent spontaneous abortions

OBJECTIVE: The risk of miscarriage is enhanced by a variety of genetic and environmental factors. Previous studies indicated an association between endothelial nitric oxide synthase (eNOS) activity, and implantation and maintenance of pregnancy, but it is rather controversial whether polymorphisms of the gene encoding for eNOS are associated with recurrent spontaneous abortions (RSA). The aim of our study was to determine whether the 27 bp intron 4 repeat polymorphism (4VNTR) and a Glu298Asp missense mutation encoded by exon 7 of the eNOS gene are associated with an increased risk for recurrent spontaneous abortions (RSA), in the Greek population. METHODS: A total of 126 women who had at least three unexplained spontaneous abortions before 20 weeks of gestation, with the same partner, were included in the study group. The control group consistent of 130 women with at least two live childbirths and without history of abortions. All patients and controls were investigated for the two polymorphisms. To genotype the cohorts we used the PCR-RFLPs method. RESULTS: The observed frequencies of bb, ba, aa genotypes of the VNTR, in intron 4, polymorphism were 0.75, 0.24, 0.01, respectively, for the patient group and 0.73, 0.24, 0.03, respectively, for the control group. The observed frequencies of GG, GT, TT of the Glu298Asp polymorphism were 0.42, 0.45, 0.13, respectively, for the patient group and 0.47, 0.45, 0.08, respectively, for the control group. Statistical analysis of the results indicates no significant difference between the two groups, for both the two studied polymorphisms. CONCLUSION: Our results do not show any influence of the two polymorphisms, VNTR in intron 4 and Glu298Asp of the eNOS gene, on early pregnancy.     

内皮型一氧化氮合酶基因第4内含子VNTR多态性与妊高征的相关性研究

目的　探讨内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)基因第 4 内含子27bp可变数目的短片段重复序列(variable number tandem repeats ,VNTR)的多态性现象与妊高征的相关性。　方法　应用PCR检测妊高征患者和健康孕妇的eNOS基因第4 内含子多态性,并采用硝酸还原酶法检测孕妇血浆 NO3-/NO2- 浓度水平,根据基因型和基因频率分组进行比较。　结果　eNOS基因VNTR 4a 等位基因频率在妊高征组明显高于对照组(16. 00%和 7. 50%,χ2 =4.63,P<0.05,比值比(OR)=2.35,95%可信度区间(CI):4.74~23.22);4a/4b+4a/4a基因型频率在妊高征组和对照组分别为 28. 00%和 13. 75% (χ2 = 5.08, P< 0.05, OR= 2. 69, 95%CI: 6. 12 ~35.44),差异有显著性;各组中的4a/4b+4a/4a基因型患者血浆中NO3-/NO2-浓度分别明显低于各4b/4b基因型患者(P<0.05)。　结论　eNOS基因第 4 内含子 VNTR与妊高征发生密切相关,并可能通过影响NO的产生在其发病机制中起到作用。     

Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis

There are controversies in reports on the association of polymorphisms in endothelial nitric oxide synthase, angiotensinogen, angiotensin receptor type 1 and angiotensin-converting enzyme genes with an increased risk of developing preeclampsia. We performed a systematic search of published case-control studies through the PubMed database up to January 2006, and report the results of a meta-analysis of polymorphisms investigated in more than five studies: Glu298Asp in eNOS gene (9 analyses involving 1055 patients and 1788 controls), Met235Thr in AGT gene (13 analyses involving 1128 patients and 2278 controls), and intron 16 insertion-deletion polymorphism in ACE gene (10 analyses involving 1121 patients and 1361 controls). Statistically significant associations with preeclampsia were identified for the Met235Thr/AGT polymorphism: OR 1.65 (95% CI 1.19, 2.29) if the polymorphism is considered under the dominant genetic model, and OR 1.54 (95% CI 1.12, 2.11) under the recessive model. For insertion-deletion/ACE polymorphism, statistical significance was demonstrated when the polymorphism was considered under the recessive model: OR 1.51 (95% CI 1.17, 1.94). No single polymorphism was identified as having a major effect.     

Lack of association between the Glu298Asp variant of the endothelial nitric oxide synthase gene and the risk of coronary artery disease among Taiwanese.

BACKGROUND AND PURPOSE: Endothelial nitric oxide synthase (eNOS) plays a key role in atherosclerosis, because its product, nitric oxide, possesses antiatherogenic properties. Recent reports of molecular genetic analysis have suggested that genetic polymorphisms of the eNOS gene may be associated with coronary artery disease (CAD) or myocardial infarction (MI). However, some studies have reported discrepant results. The aims of this study were to assess whether any association exists between the Glu298Asp variant of the eNOS gene and the risk of CAD and/or MI among Taiwanese. METHODS: The subjects included 218 CAD patients and the same number of age- and sex-matched control subjects from Taiwan. Subjects' DNA was extracted from their blood and genotypes were determined by polymerase chain reaction and restriction mapping using the restriction enzyme MboI. The alleleic and genotypic frequencies were analyzed. RESULTS: The frequencies of the eNOS genotypes were similar for CAD patients (GG:GT:TT = 81.7%:17.4%:0.9%) and controls (81.2%:17.4%:1.4%; p = 0.904). No evidence of difference was found in the frequency of the T allele between CAD patients (9.6%) and controls (10.1%; p = 0.822), or between MI patients (7.5%) and controls (p = 0.322). Subjects with the GT or TT genotype did not demonstrate an increased risk of CAD compared with those with a GG genotype (p = 0.89; OR = 0.98; 95% confidence interval, CI, 0.76-1.27) in multivariate logistic regression, or when different subgroups of age, sex, or risk factors were analyzed. CONCLUSIONS: In the present case-control study, we found no evidence of an association between the Glu298Asp variant of the eNOS gene and CAD/MI among Taiwanese.     

Genetic and environmental contributions to severe preeclampsia: lack of association with the endothelial nitric oxide synthase Glu298Asp variant in a developing country

OBJECTIVE: We recently identified a missense variant (Glu298Asp) within exon 7 of the endothelial nitric oxide synthase (eNOS) gene that is associated with severe preeclampsia in the Japanese population. Our objective was to analyze the association between the Glu298Asp eNOS gene variant and severe preeclampsia in a developing country where the incidence of preeclampsia is more frequent. METHODS: The study included 112 Bangladeshi women exhibiting severe preeclampsia and 119 control subjects. Screening for the Glu298Asp eNOS gene variant was carried out by analysis of the polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The analysis revealed that the frequencies of the Glu298Asp variant (Glu298Asp homozygotes and heterozygotes) in the preeclampsia (n = 40; 35%) and control (n = 42; 35%) groups were not significantly (p > 0.05) different. CONCLUSIONS: We conclude that the presence of the Glu298Asp eNOS gene is not a marker for the increased risk of preeclampsia in a population where the level of prenatal care is such that preeclampsia is still frequently seen.     

Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer

Objective. Nitric oxide (NO) is involved in angiogenesis and tumor growth. We attempted to establish an association between two polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and vulvar cancer.Methods. We used peripheral vanous blood sampling, DNA extraction, and polymerase chain reaction (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7 Glu298Asp polymorphisms.Results. The presence of a polymorphic NOS3*A allele (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6–2.0; P = 0.9) or a polymorphic NOS3 exon 7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3–1.0; P = 0.09) was not associated with vulvar cancer. Within the vulvar cancer group, the presence of a polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not associated with clinico-pathological parameters such as advanced tumor stage, groin lymph node involvement, tumor grading, and age at diagnosis. Survival analysis demonstrated that the presence of a polymorphic NOS3*A allele was associated with a significantly reduced disease-free survival time (P = 0.03), whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not associated with disease-free survival (P = 0.5).Conclusions. We are the first to report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation within intron 4, but not within exon 7 of NOS3, influences the length of disease-free survival, but not the biological phenotype of vulvar cancer.     

Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with severe preeclampsia

OBJECTIVES: A large number of studies suggest that abnormalities in nitric oxide (NO) synthesis may contribute to the development of preeclampsia. We recently identified a variant within exon 7 of the endothelial NO synthase (eNOS) gene: G to T conversion at nucleotide position 894 resulting in replacement of glutamic acid with aspartic acid at codon 298 (Glu298Asp). We analyzed the association between the Glu298Asp eNOS gene variant and preeclampsia. STUDY DESIGN: The study included 152 preeclampsia patients (35 mild, 80 severe, and 37 superimposed) and 170 control subjects. Screening for the Glu298Asp eNOS gene variant was carried out by analysis of polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of the Glu298Asp variant was significantly higher in the severe preeclampsia group (28.8%) than in the control (14.1%; p <. 01), superimposed preeclampsia (8.1%; p <.01), and mild preeclampsia (11.4%; p <.01) groups. CONCLUSIONS: We conclude that the presence of the Glu298Asp eNOS gene could be a marker of increased risk of developing severe preeclampsia.     

Polymorphisms in the endothelial nitric oxide synthase gene may be protective against preeclampsia in a Chinese population

The association between the endothelial nitric oxide synthase (eNOS) gene with vascular diseases in Western populations and with severe preeclampsia (PE) in the Japanese population have been demonstrated, lacing the data in Chinese population. The authors examine the association between PE and 2 polymorphisms of the eNOS gene in a Chinese population, consisting of 92 pregnant women with PE and 256 healthy controls. All were genotyped for the Glu298Asp polymorphism in exon 7 and the number of 27 base pair repeats in intron 4 of the eNOS gene. The frequencies of both the variant T allele and eNOS 4a (small allele with 4 repeats of 27 bp) were significantly lower in the PE group than in the control group. The genotype distribution of Glu298Glu, Glu298Asp, and Asp298Asp in eNOS exon 7 and bb type and ab type in eNOS intron 4 revealed statistically significant differences between control and PE groups. This is the first study to evaluate the association between 2 polymorphisms in the maternal eNOS gene with PE simultaneously in a Chinese population. Similar to the findings in Western populations, polymorphisms in the eNOS gene may be protective against PE in a Chinese population, in contrast to the results in the Japanese population.     

Recurrent early pregnancy loss and endothelial nitric oxide synthase gene polymorphisms

Objective(s): Studies on the relation between endothelial nitric oxide synthase (eNOS) activity in implantation and maintenance of pregnancy highlights the importance of eNOS gene polymorphisms in recurrent early pregnancy loss (REPL). We investigated the relationship between idiopathic REPL and polymorphisms in eNOS among South Indian women. Methods: A case-control study comprising 145 females with REPL and 99 control females. The polymorphisms studied include a 27 bp intron 4 repeat, Glu298Asp variation of exon 7 and a novel 140 A→G polymorphism in intron 6. A polymerase chain reaction-based di-deoxy dye terminator sequencing method was used for genotyping. Results: A novel A→G polymorphism was identified in intron 6. The more frequent b allele of intron 4 repeat was present at a frequency of 0.84 in cases as compared to 0.86 in controls (O.R 1.17); the G allele of exon 7 coding for the wild-type glutamate containing isoform was present at a frequency of 0.79 in cases and 0.83 in controls (O.R 1.30, CI 0.6–2.8). The intron 6 variant A allele was present at a frequency of 0.58 in cases and 0.45 in controls (O.R 0.59, CI 0.33–1.08). Overall, the polymorphism in intron 6, in homozygous condition, exhibited a significant association to the risk of REPL (O.R 0.43, CI 0.21–0.89), P: 0.021). Conclusions: The present study identifies and validates a novel polymorphism in the eNOS gene which was found associated with the risk of REPL.     

Endothelial Nitric Oxide Synthase Polymorphisms and Erectile Dysfunction: A Meta-Analysis

Introduction and AimsErectile dysfunction (ED) is a frequent disorder in men and has a serious impact on the quality of the patient's life. Recent studies have examined the relationship between endothelial nitric oxide synthase (eNOS) polymorphisms and ED. However, the results remain inconclusive. The present study aimed to offer an actual view of estimating the correlation between eNOS polymorphisms and ED.MethodsWe performed a meta-analysis to estimate the association between eNOS polymorphisms and ED risk. Databases employed for data mining until December 1, 2014 included PubMed, Web of Science, and the Chinese National Knowledge Infrastructure. Two study investigators independently conducted a literature search and data extraction. Odds ratios (ORs) with 95% confidence intervals for the risk were calculated by using a random effects model or fixed effects model.ResultsA total of 20 studies in 13 publications were included in the meta-analysis. In the overall comparison, the eNOS G984T polymorphism was associated with an increased ED risk in allele contrast, dominant, heterozygote, and homozygote models (allele contrast: OR = 1.514, 95% confidence interval [CI]: 1.019–2.248). For 4 VNTR polymorphisms, the overall analysis showed a significant association between homozygote comparison and recessive genetic model (homozygote comparison: OR = 1.917, CI: 1.073–3.424). The eNOS T786C polymorphism increased ED risk in allele contrast, homozygote, and recessive models (allele contrast: OR = 1.588, CI: 1.316–1.915). Significant heterogeneity was mainly observed in studies on the G894T polymorphism. No publication bias was detected in all of the variants.ConclusionThe eNOS polymorphisms G894T, 4 VNTR, and T786C were associated with an increased risk for ED. However, these results are still preliminary. Further studies based on different confounders and using a large population size should be conducted to generate more accurate and reliable conclusions. Liu C, Lu K, Tao T, Zhang L, Zhang X, Jiang L, Huang Y, Guan H, Chen M, and Xu B. Endothelial nitric oxide synthase polymorphisms and erectile dysfunction: A meta-analysis. J Sex Med 2015;12:1319–1328.     

Endothelial Nitric Oxide Synthase Polymorphisms and Erectile Dysfunction: A Meta-Analysis

IntroductionErectile dysfunction (ED) is a common disorder noted for affecting quality of life. Several studies have reported the influence of endothelial nitric oxide synthase (eNOS) polymorphisms on ED susceptibility. However, results of association studies with individually low statistical power are conflicting.AimOur study aimed to carry out a meta-analysis estimating the association between eNOS variants and the risk of ED.MethodsStudies regarding the association between eNOS polymorphisms and ED were searched in Medline and Embase databases. The relevant studies that met the inclusion criteria were eligible for the analysis.Main Outcome MeasuresFive genetic models and a generalized odds ratio (OR_G) were used to estimate the association between eNOS G894T and variable number of 27-bp tandem repeats in intron 4 (4 VNTR) and the risk of ED.ResultsNine articles were included in our meta-analysis. Overall, significant association between the 894T variant and an increased risk of ED was derived for all genetic contrasts except for the recessive model (allele contrast: OR = 1.64, 95% confidence interval [CI]: 1.03–2.60). The meta-analysis based on the OR_G also produced significant results: OR_G = 1.64, 95% CI: 1.03–2.61. Significant heterogeneity and publication bias were detected. The cumulative meta-analysis showed the OR increased from 2003 to 2009 and then declined in 2010. Instability in the relative change of OR was observed. Regarding 4 VNTR and its association with ED, the overall analysis showed a lack of significant association (OR = 0.96, 95% CI: 0.72–1.28). No evidence for heterogeneity among studies was observed. Subgroup analysis by ethnicity and recruitment strategy also yielded nonsignificant results.ConclusionThe result supports that G894T variant is associated with an increase in the risk of ED. No evidence for a significant association between 4VNTR and ED is observed. The results of the present meta-analysis should be interpreted with caution. Further confirmation in large and well-designed studies is needed. Wang J-L, Wang H-G, Gao H-Q, Zhai G-X, Chang P, and Chen Y-G. Endothelial nitric oxide synthase polymorphisms and erectile dysfunction: A meta-analysis.     

eNOS Gene Intron 4 VNTR and Exon 7-G894T Polymorphisms in Turkish Men with Erectile Dysfunction: A Case Control Study

IntroductionThe associations between the gene polymorphisms and erectile dysfunction (ED) are limited.AimTo examine a potential association between variable number of tandem repeats (intron 4 VNTR), G894T polymorphisms, and ED in Turkish men.MethodsSixty-four men with ED and 82 healthy men as a control group were included in the study. The patients were evaluated by medical history, International Index of Erectile Function (IIEF), serum glucose, and lipid profiles. VNTR and G894T polymorphism were assessed by isolated DNA blood samples obtained from the patient group with ED and controls.Main Outcome MeasuresAssesment of IIEF and VNTR and G894T polymorphism in the isolated DNA blood samples.ResultsGenotype distributions of endothelial nitric oxide syntase (eNOS) gene intron 4 VNTR polymorphisms in the patient group were similar to those in the healthy group (P > 0.05). The frequency of the eNOS gene intron 4 genotype was found as bb: 55 (67.1%), ab: 26 (31.7%), and aa: 1 (1.2%) in the controls and bb: 43 (67.2%), ab: 19 (29.7%), and aa: 2 (3.1%) in the patient group. The frequency of the G894T was found as gg: 61 (74.4%), gt: 21 (25.6%), and tt: 0 (0.0%) in the controls and gg: 32 (50.0%), gt: 27 (42.1%), and tt: 5 (7.8%) in the patient group (P = 0.002). The frequencies of the “t” allele were 21 (12.8%) in the control group and 37 (28.9%) in the patient group (P = 0.001). Logistic regression analysis showed that G894T polymorphism was an independent risk factor for ED.ConclusionsWe found significant differences in allelic and genotypic frequencies between patients and controls for the G894T eNOS polymorphisms. The presence of 894T allele in carriers increased the risk of ED. No association was found between VNTR polymorphism and in patients with ED. Erol B, Bozdogan G, Akduman B, Dursun A, Bozdogan S, Onem K, and Mungan A. eNOS gene intron 4 VNTR and exon 7-G894T polymorphisms in Turkish men with erectile dysfunction: A case control study. J Sex Med 2009;6:1423–1429.     

Reduced L-arginine level and decreased placental eNOS activity in preeclampsia

Nitric oxide is produced enzymatically by the nitric oxide synthase (NOS), which converts L-arginine in the presence of oxygen to L-citrulline and NO. Moreover, it has been reported that asymmetric dimethylarginine (ADMA) acts as is an endogenous inhibitor of endothelial NOS (eNOS) by competing with the enzyme for L-arginine. In this study, we measured L-arginine and ADMA in normal and preeclamptic women, and also investigated the association between the Glu298Asp eNOS gene polymorphism and preeclampsia. Finally, we assessed eNOS expression levels in the placentas of both normal and preeclamptic patients, using Western blot and immunohistochemistry. L-arginine levels were found to be significantly lower in the preeclamptic women than in the normal pregnant women (p=0.02) but there were no significant differences in ADMA levels between the normal and preeclamptic women. We also determined there to be no association between the Glu298Asp eNOS gene and preeclampsia. With regard to placental eNOS expression, we detected a lower degree of eNOS expression in the preeclamptic syncytiotrophoblasts than in the normal syncytiotrophoblasts. We suggest that reduced L-arginine levels, rather than increased ADMA levels, contribute to the development of preeclampsia, and also that decreased placental eNOS expression constitutes a characteristic finding in preeclamptic placentas.     

The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women

OBJECTIVE: To investigate whether the eNOS gene influences the risk of developing endometriosis in south Indian women. STUDY DESIGN: The single nucleotide polymorphism, Glu298Asp, in exon7 of the eNOS gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic. The genotype frequencies of the polymorphism were compared, using polymerase chain reaction and sequencing analysis. The localization and expression of eNOS in the eutopic endometrium of five cases and four controls was also analyzed using immunohistochemistry and western blotting. RESULTS: No statistically significant differences were observed in the genotype distributions and allele frequencies (p=0.3) between the cases and controls according to codominant, dominant and recessive genotype models. The localization and expression of this protein were similar in the endometrium of cases and controls. CONCLUSION: In the present study we could neither observe a difference in the eNOS expression nor establish an association between the eNOS Glu298Asp exon 7 polymorphism in south Indian women with endometriosis.     

Endothelial nitric oxide synthase gene variants and haplotypes associated with an increased risk of idiopathic recurrent miscarriage

Abstract

We investigated the association of endothelial nitric oxide synthase (NOS3) polymorphisms rs2070744 (?786T> C), 27-bp repeat 4b/4a, rs1799983 (Glu298Asp), rs3918188 (?734C> A), and rs743507 (113G> A) with idiopathic recurrent miscarriage (IRM). This was a case-control study involving women with confirmed IRM (n = 296), and 305 age- and ethnically matched control women. NOS3 rs2070744, rs1799983, rs3918188, and rs743507 genotyping was done by TaqMan assays; NOS3 4b/4a genotyping was done by PCR-ASA. A higher frequency of -786C and 298Asp alleles was seen in IRM cases, which remained associated independently with IRM on multivariate analysis. Allele and genotype distribution of 4b/4a, rs3918188 (?734C> A) and rs743507 (113A> G) were comparable between IRM cases and control women. Taking homozygous wild-type genotype as a reference, regression analysis confirmed the association of Glu298Asp and ?786T/C, and rs743507 homozygous carriers with IRM risk. Marked linkage disequilibrium was seen between tested NOS3 variants, thus allowing the construction of 5-locus [?786T> C/4b4a/Glu298Asp/-734C> A/113G> A] haplotypes. Taking the common T4bGCA haplotype as a reference, multivariate analysis confirmed the positive association of C4bTCG haplotype with IRM, after controlling for traditional covariates. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to IRM.