内皮型一氧化氮合酶基因+894G/T多态性与偏头痛发病的meta分析

目的分析内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)基因+894G/T多态性与偏头痛发病风险之间的相关性。方法本研究检索时间从建库至2016年10月。纳入评估eNOS多态性(+894G/T)与偏头痛发病风险之间相关性的病例对照研究。初筛得到365篇全文,经筛选后最终5篇纳入meta分析。异质性分析采用I~2检验,文献质量评估采用英国牛津循证医学中心文献严格评价项目。结果与GG+GT基因型相比,TT基因型增加有先兆偏头痛(migraine with aura,MA)的发生风险(OR=1.56,95%CI 1.11~2.20;I~2=0%,P=0.01)。在非高加索人群中,GT+TT基因型可增加偏头痛发病风险(OR=1.53,95%CI 1.08~2.16;I~2=0%,P=0.02)。结论本研究提示内皮型一氧化氮合酶基因+894G/T多态性与偏头痛发病风险之间有一定的关系,并且可能因人群遗传背景的不同与偏头痛亚型有一定关联。     

内皮源性一氧化氮合酶基因多态性与缺血性脑卒中相关性研究

目的通过病例对照研究,探讨内皮源性一氧化氮合酶(eNOS)基因多态性与缺血性脑卒中的关系。方法采用聚合酶链反应(PCR)和限制性片断长度多态性(RFLP)技术,对452例缺血性脑卒中患者和153例健康对照人群的eNOS基因rs3918181位点进行基因多态性检测。结果大动脉粥样硬化型脑梗死组的基因型与等位基因频率与正常对照组比较P>0.05,无统计学意义。腔隙性脑梗死组eNOS基因AA AG基因型频率明显高于对照组,相对于GG基因型,暴露于AA AG基因型人群的OR值为1.644(95%CI 1.124～2.405)。腔隙性脑梗死A等位基因频率也显著高于对照组,相对于G等位基因,A等位基因OR值为1.419(95%CI 1.061～1.898)。结论内皮源性一氧化氮合酶(e-NOS)基因rs3918181位点多态性与腔隙性脑梗死相关;A等位基因可能增加中国汉族人罹患腔隙性脑梗死的风险。     

蒙古族脑卒中患者5,10-亚甲基四氢叶酸还原酶、内皮型一氧化氮合酶、β-1肾上腺素能受体和G蛋白β3亚单位基因多态性的研究

目的 研究蒙古族脑卒中患者5,10-亚甲基四氧叶酸还原酶(MTHFR)基因C677T、内皮型一氧化氮合酶(eNOS)基因G894T、β-1肾上腺素能受体(ADRB1)基因G1165C、G蛋白β3亚单位(GNB3)基因C825T位点的多态性.方法 用PCR方法检测68例蒙古族脑卒中患者和107名健康对照者上述4个基因位点的多态性.用Logistic回归分析基因多态性与脑卒中的关系.结果 脑卒中组eNOS基因G894T位点T等位基因频率显著高于正常对照组(P<0.01);两组MTHFR基因C677T位点、ADRB1基因G1165C位点、GNB3基因C825T位点基因型及等位基因频率比较差异无统计学意义.Logistic回归分析显示eNOS基因G894T位点GT基因型是脑卒中发病的独立危险因素(OR为4.550,95%CI为1.324～15.633,P<0.05).结论 eNOS基因G894T GT基因型是蒙古族脑卒中患者发病的独立危险因素;MTHFR基因C677T位点、ADRB1基因G1165C位点、GNB3基因C825T位点多态性与蒙古族脑卒中无明显关系.     

血管紧张素原基因多态性和α-内收蛋白基因多态性与动脉粥样硬化性脑梗死的相关性

目的探讨血管紧张素原(AGT)基因T174M、M235T及α-内收蛋白基因G460T多态性与动脉粥样硬化性脑梗死(ACI)之间的关系。方法采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测396例ACI患者(病例组)和360例健康体检者(对照组)的AGT基因T174M、M235T及α-内收蛋白基因G460T基因多态性。结果将AGT基因T174M多态位点与内收蛋白G460T多态位点进行联合基因型分析,TM+GT、TM+TT基因型组合在两组间分布有显著性差异(OR=3.253,95%CI:1.384~7.646,P0.05;OR=3.791,95%CI:1.041~13.286,P0.05)。将AGT基因M235T多态位点与α-内收蛋白G460T多态位点进行联合基因型分析,只有GG+MM基因型组合在两组间分布有显著性差异(P0.05)。结论 AGT基因T174M位点与内收蛋白G460T位点联合基因型TM+GT、TM+TT基因型组合为ACI的危险因素;α-内收蛋白G460T位点与AGT基因M235T位点联合基因型GG+MM野生基因型组合为ACI发生的保护因素。     

NOS3基因多态性与血脂、缺血性脑卒中的相关性研究

目的为了探索NOS3基因G894T多态性与缺血性脑卒中的关联,以及与血脂的关系。方法聚合酶链式反应-限制性片段长度多态性(PCR-RFLP),琼脂糖凝胶电泳检测100例缺血性脑卒中患者和对照组80例健康志愿者的NOS3基因G894T多态性。自动生化分析仪检测血脂指标。结果 (1)卒中组与对照组相比GT(27/100和22/120)和TT(7/100和2/120)基因型分布频率较高(P 0. 05)。T等位基因分布在卒中组(20. 5%)也显著高于对照组(10. 83%)(P 0. 01);(2)卒中组中TT基因型携带者血脂水平TC和LDL-C显著高于GG和GT基因型患者,而其他血脂水平无显著差异;(3)关联分析显示TT基因型与卒中患病风险具有相关性(P 0. 05)。结论 NOS3基因多态性与缺血性脑卒中发病存在关联,TT基因型携带者患病风险高于GG基因型携带者。     

精神分裂症患者一级亲属的探索性眼球运动与eNOS基因G894T多态性研究

目的：探讨内皮型一氧化氮合成酶（eNOS）基因G894T多态性与精神分裂症患者一级亲属探索性眼球运动（EEM）缺陷的相关性。方法：共收集精神分裂症患者一级亲属193名,正常对照家系一级亲属150名,进行EEM检查,并采用基因芯片技术进行eNOS基因型检测。结果：精神分裂症一级亲属EEM异常率（52%）显著高于正常对照家系一级亲属EEM异常率（15%）（χ^2=52,P〈0.01）;EEM异常者与EEM正常者eNOS基因GT＋TT基因型频率及T等位基因频率差异无显著性（χ^2=2.08,P〉0.05;χ^2=2.55,P〉0.05）。在101名精神分裂症一级亲属的EEM异常者中,对30名GT＋TT基因型携带者与71名GG基因型携带者的凝视点数（NEF）、反应性探索评分（RSS）比较,差异均无显著性（P均〉0.05）。结论：eNOS基因G894T多态性与精神分裂症患者一级亲属的EEM缺陷可能无关。     

神经元型一氧化氮合酶基因多态性与脑梗死的相关性

目的探讨神经元型一氧化氮合酶(NOS1)基因多态性与脑梗死发病的关系。方法以rs9658281和rs2682820位点为遗传标记,采用聚合酶链式反应(PCR)和限制性片断长度多态性(RFLP)技术检测605例脑梗死患者和313例对照组人群的基因型。结果Rs9658281位点G等位基因频率较对照组明显增高(χ2=3.906,P=0.048,OR=1.362,95%CI1.003～1.850),这种差异在女性明显(χ2=6.689,P=0.010,OR=1.913,95%CI1.170～3.167)。Rs9658281位点的GG基因型频率较对照组明显增高(χ2=5.322,P=0.021,OR=1.473,95%CI1.060～2.047),这种差异在女性明显(χ2=9.299,P=0.002,OR=2.315,95%CI1.349～3.972)。经过多因素回归分析调整了传统危险因素的影响后,两组间仍有显著性差异(P=0.023)。Rs2682820位点的基因型频率和等位基因频率在脑梗死组和对照组的分布无显著差异(P>0.05)。结论神经元型一氧化氮合酶(NOS1)基因rs9658281位点多态性与脑梗死的发病可...     

中国人群中一氧化氮合酶Ⅲ基因多态性与阿尔茨海默病的关联性研究

目的:研究中国人群中一氧化氮合酶Ⅲ(NOS-Ⅲ)298G/T多态性与阿尔茨海默病(Alzheimerdisease,AD)发病的相关性;方法:通过实时定量荧光PCR和GeneAmp5700SDS软件检测530例AD患者和601例非痴呆对照者NOS-Ⅲ298G/T的基因多态性,并应用Logistic回归模型分析其与AD发病的相关性;结果:NOS-Ⅲ的G/G、G/T和T/T在AD组和对照组中分布差异无统计学意义(P>0.05),没有发现NOS-Ⅲ298G/T基因多态性与AD发病存在关联性;调整年龄和性别的影响后,G/G基因型并不是AD发病的危险因素,其OR值分别为1.17,P=0.73。结论:在中国人群中NOS-Ⅲ298G/T基因多态性与AD的发病不存在关联性。     

CTLA-4+49A/G多态性与多发性硬化相关性的meta分析

目的探讨CTLA-4+49A/G多态性与多发性硬化(MS)的相关性。方法通过检索PubMed数据库收集有关CTLA-4+49A/G多态性与MS相关的病例-对照研究,文献检索时间从建库至2013-09期间。采用RevMan 4.2统计软件对其结果进行分析。结果共纳入25个以高加索和亚洲人群为研究对象的MS病例对照研究,包括高加索MS患者4663例和高加索健康对照4249例,亚洲MS患者563例和亚洲健康对照667例。各研究的等位基因和基因型频数结果未见明显发表偏倚。25个研究合并后,G/A、GG+GA/AA、GG/GA+AA合并的OR值分别为1.00(95%CI为0.96~1.06,P=0.91)、1.01(95%CI为0.93~1.10,P=0.73)、0.99(95%CI为0.88~1.10,P=0.81)。高加索人群的研究合并后,G/A、GG+GA/AA、GG/GA+AA合并的OR值分别为1.00(95%CI为0.94~1.06,P=0.99)、0.99(95%CI为0.91~1.08,P=0.85)、1.01(95%CI为0.90~1.14,P=0.83)。亚洲人群的研究合并后,G/A、GG+GA/AA、GG/GA+AA合并的OR值分别为1.03(95%CI为0.87~1.22,P=0.73)、1.22(95%CI为0.95~1.57,P=0.12)、0.83(95%CI为0.61~1.12,P=0.22)。结论 CTLA-4+49A/G多态性与MS无相关性。     

内皮一氧化氮合酶基因G894T多态性与动脉瘤性蛛网膜下腔出血的相关性研究

目的 研究eNOS基因第7外显子G894T多态性与动脉瘤性蛛网膜下腔出血(aSAH)的相关性.方法 利用聚合酶链反应(PCR)、琼脂糖凝胶电泳验证PCR反应产物,限制性片段长度多态性(RFLP)分析比较aSAH患者和对照者eNOS基因型的构成及等位基因频率的分布.结果 aSAH患者组的GT+TT基因型和T等位基因频率显著高于对照组,差异具有统计学意义.基因型分布在破裂的颅内动脉瘤直径大小之间差异无统计学意义,但是与aSAH患者预后相关.结论 eNOS基因G894T多态性可能是asAH发病的危险因子之一,GT+TT基因型与不良预后密切相关.     

Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke

OBJECTIVE: Endothelial nitric oxide synthase (eNOS), which produces NO, plays an important role in the endothelial function under a wide range of physiological conditions. eNOS exon 7 polymorphism (Glu298Asp, G894T) has been considered to influence the risk of coronary artery disease. Alone, however, it has not been shown to be a genetic risk factor for ischaemic stroke. With the assumption of additive interactions, we examined whether the eNOS G894T or eNOS 894TT genotypes in combination with the methylenetetrahydrofolate reductase 677TT (MTHFR 677TT) or angiotensin-converting enzyme (ACE) D/D genotype could contribute to acute ischaemic stroke. MATERIAL AND METHODS: The data on 407 consecutive patients with acute ischaemic stroke who had never suffered a previous stroke event were analysed. As a control group, 295 stroke and neuroimaging alteration-free Caucasian subjects were examined. With the use of the PCR technique, the eNOS G894T, eNOS 894TT, MTHFR 677TT and ACE D/D mutations, as unfavourable common genotypes were determined in the participants. Logistic regression models were used to evaluate the roles of the genotypes and their combinations in the development of ischaemic stroke. RESULTS: The MTHFR C677TT genotype combined with the eNOS G894T or eNOS 894TT genotypes occurred significantly more frequently in the subjects with ischaemic stroke (7.1%; P < 0.025) than in the control group (3.1%). The co-occurrence of the ACE D/D genotype and eNOS G894T or eNOS 894TT was calculated to be more frequent in the ischaemic stroke group (20.9%, P < 0.0001) than in the control group (5.4%). CONCLUSION: The eNOS G894T or eNOS 894TT genotypes in combination with the MTHFR 677TT or ACE D/D genotype increases the risk of ischaemic stroke.     

The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration

Background and aims:  Neuronal nitric oxide synthase (NOS)1 C276T polymorphism was shown to increase the risk for frontotemporal lobar degeneration (FTLD). In the brain, both NOS1 and NOS3 (endothelial isoform) have been detected. The distribution of NOS3 G894T (Glu298Asp) and T-786C single nucleotide polymorphisms (SNPs) was analyzed in a population of 222 patients with FTLD compared with 218 age-matched controls to determine whether they could influence the susceptibility to develop the disease.
Results:  A statistically significant increased frequency of the NOS3 G894T SNP was observed in patients as compared with controls (40.0 vs. 31.4%, P  =   0.011, OR: 1.65, CI: 1.13–2.42). Conversely, the distribution of the T-786C SNP was similar in patients and controls. No differences were observed stratifying according to gender.
Discussion:  The NOS3 G894T polymorphism likely acts as risk factor for sporadic FTLD, but studies in larger populations are needed to confirm these preliminary findings.     

Endothelial nitric oxide synthase Glu298Asp, 4b/a,and −786T>C gene polymorphisms and the risk of ischemic stroke

Saidi S, Mallat SG, Almawi WY, Mahjoub T. Endothelial nitric oxide synthase Glu298Asp, 4b/a, and ?786T>C gene polymorphisms and the risk of ischemic stroke
Acta Neurol Scand: 2010: 121: 114–119.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background and purpose – Endothelial nitric oxide synthase (eNOS) gene polymorphisms were associated with reduced NO production, and were evaluated as risk factors for ischemic stroke (IS). We investigated the association between eNOS gene ?786T>C (promoter), 27‐bp repeat 4b/4a (intron 4), and Glu298Asp (exon 7) polymorphisms with IS in 329 IS patients and 444 controls. Materials and methods – Glu298Asp and ?786T>C genotyping was done by PCR‐RFLP, 4b/4a was assessed by PCR–ASA. The contribution of eNOS polymorphisms to IS was analyzed by haplotype and multivariate regression analysis. Results – Higher frequency of 298Asp allele was seen in IS patients (P = 1.2 × 10^?10), which remained independently associated with IS on multivariate analysis after controlling for traditional cerebrovascular risk factors. Allele and genotype distribution of 4b/4a and ?786T>C polymorphisms were comparable between patient and controls. Significantly higher prevalence of 298Asp/4b/?786T and 298Asp/4b/?786C haplotypes were seen in IS cases, thus conferring a disease susceptibility nature to these haplotypes. Multivariate regression analysis confirmed the association of 298Asp/4b/?786T and 298Asp/4b/?786C haplotypes, and in addition identified 298Asp/4a/?786T haplotype to be independently associated with IS, after controlling for traditional cerebrovascular risk factors. Conclusions – Genetic variation at the eNOS locus represent genetic risk factor for increased susceptibility to IS.     

Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease

INTRODUCTION: Endothelium-derived nitric oxide (NO) is synthesized from l-arginine by endothelial nitric oxide synthase (eNOS) encoded by the eNOS3 gene on chromosome 7. The effects of the eNOS polymorphisms with the risk of coronary artery disease are conflicting. In this study, we investigated the association of the eNOS genotypes with coronary artery disease in Koreans. MATERIALS AND METHODS: A case-control study was performed to evaluate the association between the eNOS -786T>C, 4a4b, or 894G>T polymorphism and coronary artery disease. 147 consecutive patients with coronary artery disease and 222 healthy controls were recruited. The genotypes of eNOS -786T>C and 894G>T polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes of a 27 bp insertion/deletion in intron 4 (eNOS 4a4b) were determined by the banding pattern on gel electrophoresis. RESULTS: The eNOS -786T>C (odds ratio [OR]; 1.61, 95% confidence interval [CI]; 0.97-2.69), 894G>T (OR; 1.12, 95% CI; 0.65-1.92) and 4a4b (OR; 1.44, 95% CI; 0.87-2.39) polymorphisms were not an independent predisposition factor to coronary artery disease. However, a subgroup analysis adjusted with various cardiovascular risk factors confirmed positive association of the -786T>C polymorphism in CAD patients with hypertension and a smoking history and also a significant association of the intron 4 genotypes with a smoking history, but no significance has been found in the eNOS polymorphisms of 894G>T upon any risk adjustment. In this study we also found that the distribution of heterozygotes (-786TC, 894GT, and 4a4b) and variant homozygotes for the -786C, 894T, and intron 4a alleles of eNOS in Koreans were significantly lower than in Caucasian populations. CONCLUSIONS: The present study demonstrates that polymorphisms of the eNOS -786T>C and 4a4b are associated with coronary artery disease with adjustments for cardiovascular risk factors in the Koreans.     

Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. The GENIC Investigators

BACKGROUND AND PURPOSE: Nitric oxide (NO) synthesized by endothelial constitutive NO synthase (ecNOS) plays a key role in vascular regulation and atherosclerosis. Little is known concerning the role of the ecNOS gene (NOS3) as a risk factor for brain infarction (BI). Our aim was to investigate the relation between the Glu298Asp polymorphism in exon 7 of NOS3 with BI and its subtypes. METHODS: Patients (n=460; cases) with BI were consecutively recruited and classified into etiological subtypes. Control subjects (n=460; controls) without a history of stroke were recruited among individuals hospitalized at the same institutions and individually matched on age, sex, and center. Genotypes of the polymorphism were determined by polymerase chain reaction. RESULTS: The distribution of genotypes was significantly different between cases and controls (P=0.008); the GG genotype was more frequent in cases (46.1%) than in controls (35.4%; OR, 1.56; 95% CI, 1.19 to 2.04). Among subtypes, the frequency of the GG genotype was significantly higher in cases than in controls in the lacunar subtype (OR, 2.00; 95% CI, 1.05 to 3. 80); in this group, the relation between BI and LDL level was stronger among carriers of the GG genotype than among noncarriers (P for interaction, 0.05). CONCLUSIONS: Homozygosity for the G allele of the Glu298Asp polymorphism in NOS3 was associated with BI, and especially with lacunar stroke. Our findings suggest that genetic susceptibility and LDL cholesterol have a synergistic relation. Although these findings should be replicated in a larger sample of subjects and the functionality of the Glu298Asp polymorphism has not been established, these results may help us to understand the cause of the arteriolopathy underlying lacunae and have future implications in their treatment and prevention.     

Lack of evidence for contribution of Glu298Asp (G894T) polymorphism of endothelial nitric oxide synthase gene to plasma nitric oxide levels

INTRODUCTION: Both positive and negative associations between a rare allele of 27-bp repeat polymorphism in intron 4 of endothelial nitric oxide synthase and plasma nitric oxide (NO) levels were previously reported, and further, these conflicting results were suggested to be partly accounted for smoking status of subjects. However, the genetic contribution of Glu298Asp (G894T) polymorphism to plasma NO levels with respect to smoking status has not been published. METHODS: In a group of 411 healthy Korean subjects aged 19-81 years, the end product of NO (NO(x): nitrite plus nitrate) as an index of plasma NO levels was measured by the Griess method. The genotypes of G894T polymorphism were determined by the banding patterns on gel electrophoresis after restriction enzyme digestion. RESULTS: Comparison of plasma NO(x) levels revealed no significant differences across the genotypes and alleles of G894T polymorphism, which is independently of smoking status. However, significant differences in plasma NO(x) levels between nonsmokers and smokers were observed (P = 0.0040). Furthermore, only the common G allele was found to be responsible for these differences. Multiple regression analysis showed that the most independent contributing factor for plasma NO(x) levels was smoking (P = 0.0119) and followed by triglycerides (P = 0.0384). CONCLUSIONS: Our results indicate no substantial effect of G894T polymorphism on the variance of plasma NO(x) levels in healthy Korean population.     

No evidence for an association between the Glu298Asp polymorphism of the NOS3 gene and Alzheimer's disease

Summary. Recently a significant association of a missense mutation (Glu298Asp) of the endothelial nitric oxide synthase (NOS3) gene with late-onset Alzheimer's disease (LOAD) was reported. We tried to replicate this finding in a Japanese sample of 121 patients with LOAD, 51 with early-onset AD (EOAD), and 165 medical controls. However, the genotype and allelic distributions for the Glu298Asp polymorphism were similar for these three groups, suggesting that the Glu298Asp polymorphism of the NOS3 gene has no relevance to the development of AD in Japanese. Received March 20, 2000; accepted May 22, 2000     

Association study of the GAB2 gene with the risk of developing Alzheimer's disease

The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE varepsilon4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT+TT)=1.3, 95% CI 1.0-1.6, p=0.09) and the G allele frequency (OR=1.3, 95%CI 1.0-1.6, p=0.05) in varepsilon4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.