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.     

白细胞介素6基因多态性与动脉粥样硬化性脑梗死的关系

目的探讨IL-6-572C/G基因多态性与中国湖南地区汉族人群动脉粥样硬化性脑梗死(atherosclerotic cerebral infarction,ACI)的关系。方法在湖南汉族人群中筛选199例脑梗死患者为脑梗死组,196名健康体检者为对照组,采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length poly-morphism,PCR-RFLP)方法测定IL-6-572C/G基因多态性。结果脑梗死组与对照组间比较,IL-6-572C/G基因型分布存在统计学差异(2=5.120,P<0.05),IL-6-572C/G基因C和G等位基因频率也存在统计学差异,(C和G等位基因频率,脑梗死组为0.741、0.259,对照组为0.816、0.184)(2=5.491,P<0.05)。G等位基因携带者发生脑梗死的风险是C等位基因的1.552倍(OR=1.552,95%CI:1.092-2.315)。结论 IL-6-572C/G基因多态性与ACI发病有关,可能是中国湖南地区汉族人群ACI发病的遗传易感基因。     

汉族人白细胞介素-6-174G/C基因多态性与颅内动脉瘤的关联性研究

目的 探讨汉族人白细胞介素-6-174G/C(IL-6-174G/C)基因多态性与颅内动脉瘤(IA)的相关性.方法 用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对182例颅内动脉瘤患者(颅内动脉瘤组)和182名健康者(对照组)的IL-6-174G/C的基因多态性进行分析,运用统计学方法分析基因与疾病的相关性.结果 IL-6-174G/C基因型的分布频率与对照组比较有统计学意义(P<0.001),IL-6-174(G/C)G等位基因频率为69.51%,对照组为56.87%,两组比较有统计学差异(P<0.001).结论 IL-6-174G/C基因多态性与颅内动脉瘤的发病有一定关系,考虑C等位基因频率增高与颅内动脉瘤的发病有关.     

血管内皮生长因子基因多态性与动脉瘤性蛛网膜下腔出血的相关性研究

目的探究血管内皮生长因子(VEGF)基因多态性与动脉瘤性蛛网膜下腔出血(a SAH)的相关性。方法采用病例对照的研究方法,实验组为158例a SAH患者,均行颅脑CT检查证实为a SAH,并经脑血管造影证实是否存在颅内动脉瘤;对照组为146名健康成年人。取两组外周血,提取基因组DNA。检测VEGF2578C/A的基因型及等位基因分布频率。比较各位点基因型频率的观察值与预期值并进行卡方检验和Hardy-Weinberg平衡分析,以及VEGF基因型与a SAH的相关性。结果 1对照组VEGF的2个多态位点的基因型频率分布符合Hardy-Weinberg平衡(P0.05)。2VEGF2578C/A基因型及等位基因分布,CC+CA基因型频率,实验组显著高于对照组(P0.05);实验组的C等位基因频率明显高于对照组,两组比较差异有统计学意义(χ2=4.256,P=0.037)。结论 VEGF基因启动子区-2578C/A多态性可能与aSAH有关。     

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.     

内皮型一氧化氮合成酶基因G298A、-786T>C多态性与缺血性脑卒中的关系

目的探讨一氧化氮合成酶基因G298A和-786T>C多态性与缺血性脑卒中(ischemic stroke,IS)的关系。方法采用病例对照研究,选取138例缺血性脑卒中患者和100例健康人,应用聚合酶链技术(PCR)和限制性片段长度多态性(restriction fragment length Polymorphism,RFLP)技术,对其进行一氧化氮合成酶基因多态性检测,并比较2组间基因型和等位基因分布差异。结果一氧化氮合成酶基因位点上G298A、-786T>C基因型分布2组比较差异无统计学意义(其P值分别为0.80、0.97),longistic回归分析后均P>0.5(0.41、0.32);在缺血性脑卒中和健康人群中以GG-TT基因型分布最多(分别占72.06%和67.00%),在2个基因位点间等位基因比较,差异无统计学意义(P>0.05)。传统的危险因素如吸烟、血脂及血压等,是影响缺血性脑卒中的重要危险因素。结论一氧化氮合成酶基因上G298A、-786T>C与缺血性脑卒中无相关,但人群中仍以等位基因G和T分布最多,提示G和T可能是缺血性脑卒中的保护基因。     

白细胞介素-6基因-174G/C多态性与阿尔茨海默病及血管性痴呆的关联研究

目的 探索白细胞介素-6(IL-6)基因启动子区-174G/C多态性与阿尔茨海默病(AD)、血管性痴呆(VD)的关系.方法 采取病例对照研究方法 ,以广州地区流行病学调查中诊断的161例AD、54例VD患者和247名健康老年人为研究对象,用聚合酶链反应-限制性片段长度多态性技术检测IL-6基因-174G/C多态性.结果 (1)所有研究对象均无C/C基因型.(2)AD组C等位基因频率(0.9%)及G/C基因型(1.9%)高于正常对照组(均为0),但差异无统计学意义(P＞0.05);按是否携带载脂蛋白E(Apo E)ε4进行分层,差异仍无统计学意义(P＞0.05).(3)VD患者C等位基因(1.9%)频率及G/C基因型(3.7%)高于正常对照组(均为0),差异有统计学意义(均P＜0.05).(4)中、重度AD患者含ε4等位基因的频率(23.9%)高于对照组(14.7%,P＜0.05).结论 IL-6基因-174G/C多态性不是广州地区汉族人群AD发病的危险因素,但与VD可能有关联.     

白细胞介素-6 -634 C/G基因多态性与脑梗死的关系

目的 探讨中国湖南汉族人群IL-6-634C/G基因多态性与脑梗死的关系.方法 应用聚合酶链反应-限制性酶切片段长度多态性分析(PCR-RFLP)方法对中国湖南汉族314例脑梗死患者和326例与之年龄、性别等相匹配的健康体检者进行IL-6-634C/G基因多态分析,并经基因测序证实.结果 在中国湖南汉族人群中,IL-6-634C/G存在GG、CG、CC 3种基因型;3种基因型和等位基因频率在脑梗死组和对照组之间比较差异无显著性(P>0.05).结论 IL-6-634C/G基因多态性可能不是湖南汉族人群脑梗死的遗传易感基因.     

蛛网膜下腔出血并发急性脑积水的治疗方法及可行性探讨

目的探讨动脉瘤性蛛网膜下腔出血并发急性脑积水(未处理动脉瘤前急诊行脑室外引流术)治疗的方法及可行性。方法收集我院2005-04—2015-10收治的94例动脉瘤性蛛网膜下腔出血并发急性脑积水患者,其中47例入院后急诊行脑积水外引流术,术后再行动脉瘤闭塞术为实验组;47例先给予保守治疗,待动脉瘤闭塞术治疗后再行脑积水外引流术为对照组。结果实验组47例术后CT复查提示脑室缩小至正常,脑积水缓解,意识评分较入院时上升。全部病例于术后3d行全脑血管造影术,1周内行动脉瘤闭塞术治疗。实验组4例在动脉瘤治疗前出现颅内动脉瘤再发出血,病情加重。实验组术后1周内动脉瘤再发破裂出血与文献大宗病例报告的出血率差异无统计学意义(P0.05),不增加破裂动脉瘤再出血风险;与对照组比较,术后实验组并发症发生率8.51%明显低于对照组17.02%,差异有统计学意义(P0.05);2组治疗后Barthel指数评分差异有统计学意义(P0.05);2组治疗后GOS评分差异有统计学意义(P0.05)。结论动脉瘤性蛛网膜下腔出血并发急性脑积水,急诊行脑室外引流术后再行动脉瘤治疗安全可靠,能促进患者神经功能恢复。     

MMP-2、MMP-9基因多态性与缺血性脑卒中临床分型及预后

目的探讨基质金属蛋白酶2(Matrix Metalloproteinase-2,MMP-2)基因C1306T、C735T和MMP-9基因C1562T多态性位点与缺血性脑卒中的关系。方法采用限制性片段长度多态性分析技术,检测缺血性脑卒中组232例和健康对照组235例MMP-2基因C1306T、C735T和MMP-9基因C1562T多态的分布。结果缺血性脑卒中组和对照组MMP-2 C1306T基因型和等位基因频率分布无统计学意义。在动脉粥样硬化性血栓性脑梗死组MMP-9 C1562T的CT+TT基因型频率和T等位基因频率、MMP-2 C735T的CC基因型频率和C等位基因频率明显高于对照组(P<0.05),而在脑栓塞组、腔梗组差异无统计学意义(P>0.05)。多因素Logistic回归分析,MMP-2、MMP-9不同基因型别与缺血性脑卒中预后无显著相关性(P>0.05)。结论 MMP-2 C735T的C等位基因、MMP-9 C1562T的T等位基因是动脉粥样硬化性血栓性脑梗死的遗传易感基因之一。MMP-2、MMP-9基因多态性与缺血性脑卒中预后无关。     

Association of interleukin-6-572G/C gene polymorphisms in the Cantonese population with intracranial aneurysms

Recent studies have demonstrated that cytokines play an important role in the pathogenesis of intracranial aneurysms (IAs). Interleukin-6 (IL-6) is an important proinflammatory cytokine. In our study, we investigated the association of genetic variants within the gene encoding interleukin-6-572G/C (IL-6-572G/C) with IAs in the Cantonese population. The IL-6-572G/C gene polymorphisms in 182 IA cases and 182 controls were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Differences in genotype and allele frequencies between patients and controls were tested. There is significant difference of IL-6-572G/C genotype frequencies in IA group compared with control group (P=0.01), and significant difference of IL-6-572G/C allele frequency in IA group (11.54%) compared with control group (4.95%) (P=0.001). Polymorphisms within IL-6-572G/C gene are associated with IAs in the Cantonese population suggesting that the IL-6-572G/C gene is an important candidate gene for IAs.     

Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm.

Rupture of an intracranial aneurysm (subarachnoid hemorrhage) is a potentially devastating condition frequently complicated by delayed cerebral ischemia from sustained contraction of intracranial arteries (cerebral vasospasm). There is mounting evidence linking the formation of intracranial aneurysms and the pathogenesis of post-subarachnoid hemorrhage vasospasm to aberrant bioavailability and action of the vasodilator molecule nitric oxide generated by isoforms of nitric oxide synthase. In humans, the gene encoding the endothelial isoform of nitric oxide synthase (eNOS) is known to be polymorphic, with certain polymorphisms associated with increased cardiovascular disease susceptibility. In this prospective clinical study involving 141 participants, we used gene microarray technology to demonstrate that the eNOS gene intron-4 27-base pair variable number tandem repeat polymorphism (eNOS 27 VNTR) predicts susceptibility to intracranial aneurysm rupture, while the eNOS gene promoter T-786C single nucleotide polymorphism (eNOS T-786C SNP) predicts susceptibility to post-subarachnoid hemorrhage vasospasm. We believe that genetic information such as this, which can be obtained expeditiously at the time of diagnosis, may be used as a helpful adjunct to other clinical information aimed at predicting and favorably modifying the clinical course of persons with intracranial aneurysms.     

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.     

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.     

The role of endothelial nitric oxide synthase (eNOS) genetic variants in European patients with intracranial aneurysms.

The endothelial nitric oxide synthase (eNOS) gene harbors three well-characterized genetic variants, which have been reported to be associated with various vascular diseases. Recently, conflicting results have been published relating to the role of these genetic variants in the pathogenesis of intracranial aneurysms (IA). Therefore, we analyzed these variants in a large European population of IA patients and controls. In all, 142 patients with IA and 190 controls were enrolled in our study. The -786T>C and 894G>T single-nucleotide polymorphisms (SNPs) were analyzed by direct sequencing of the corresponding sections in the genomic DNA. A variable number tandem repeat (VNTR) located in intron 4 of the gene and consisting of either four or five 27-base pair (bp) repeats was analyzed by polymerase chain reaction amplification and electrophoresis using ALF sequencertrade mark equipment. Genotype and allele frequencies were determined, and the frequencies in cases and controls were compared. In addition, haplotypes were constructed. There were no deviations from Hardy-Weinberg equilibrium. Genotype and allele frequencies did not differ significantly between cases and controls in any sample group or after stratification for multiple IA or aneurysm size. No single haplotype was significantly associated with the phenotype of an IA. The -786T>C, 894G>T, and 27-bp VNTR genetic variants of the eNOS gene are not associated with IA in the European population.     

介入栓塞治疗不同直径颅内动脉瘤的临床效果观察

目的 观察介入栓塞治疗对不同直径颅内动脉瘤的临床效果及安全性。方法 回顾性分析本院在2015年8月-2017年1月收治的87例颅内未破裂动脉瘤患者的临床资料,根据动脉瘤直径不同分为小型动脉瘤组(瘤体直径≤3 mm)41例,中大型动脉瘤组46例,均行介入栓塞治疗; 比较2组患者栓塞效果、并发症、复发率及预后。结果 术后6个月小型动脉瘤组完全栓塞率为100%,中大型动脉瘤组完全栓塞率为91.30%(42/46),动脉瘤瘤颈残留3例(6.52%),动脉瘤腔残留1例(2.17%),2组比较无明显差异(P>0.05); 小型动脉瘤组单纯弹簧圈栓塞16例,支架辅助弹簧圈栓塞25例,中大型动脉瘤组单纯弹簧圈栓塞23例,支架辅助弹簧圈栓塞18例,球囊辅助弹簧圈栓塞5例,2组比较也无明显差异(P>0.05); 小型动脉瘤组并发症发生率较中大型动脉瘤组低(7.32% vs 15.22%),但无明显差异(P>0.05); 术后6个月小型动脉瘤组无复发病例,中大型动脉瘤组复发率为8.69%(4/46),2组比较也无明显差异(P>0.05); 术后30 d,小型动脉瘤组GCS预后评分中恢复良好例数明显多于中大型动脉瘤组(87.80% vs 58.69%),2组比较有明显差异(P<0.05)。结论 介入栓塞治疗对不同直径的颅内动脉瘤均具有较好的疗效,但小型动脉瘤预后较好。     

The interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are related to cerebral aneurysms

Background and aims

An important part is played by inflammation in intracranial aneurysm formation. The hypothesis that there is an association of the proinflammatory cytokine interleukin‐6 (IL‐6) genotypes (−572G>C and −174G>C) with intracranial aneurysms was tested.

Methods

IL‐6 genotypes were determined in 91 Caucasian patients with aneurysms and compared with 2720 healthy UK controls.

Results

For both polymorphisms, the distribution of the genotypes and estimated allele frequency were different between the control group and the aneurysm group. For −572G>C, a higher frequency of the C allele (p = 0.001) and more people homozygous for the C allele were found among those with aneurysms than among the controls (4.4% v 0.3%, p = 0.001). For −174G>C, more people homozygous for the C allele were found among the controls than among those with aneurysm (18% v 7%, p = 0.007). The 572C/174G haplotype was associated with an increased risk of aneurysms, with the relative risk compared with the common haplotype being 1.89 and that for the −572G/174C haplotype being 0.58 (p<0.0005).

Conclusion

This is the first study to show that IL‐6 promoter polymorphisms are associated with intracranial aneurysmal disease. Whether this association is with the development, progression or rupture of such aneurysms, or represents survivor bias, is unclear.Although the pathogenesis of cerebral aneurysms is likely to be multifactorial, vessel inflammation is believed to make a substantial contribution.^1,2 The pleiotropic cytokine interleukin‐6 (IL‐6) may be essential in this regard, orchestrating the synthesis of the full spectrum of acute‐phase proteins and mediating associated endothelial dysfunction by releasing chemokine and adhesion molecules.To date, two common functional polymorphisms of the IL‐6 gene promoter have been identified, −572G>C and −174G>C, each consisting of the substitution of a single nucleotide.^3,4 Both the −174C and −572C alleles are functional in vitro^4,5 and have been associated with greater in vivo IL‐6 synthesis in an inflammatory state.^3,5,6 The −174C allele is reported to be associated with higher risk of coronary artery disease in both case–control⁷ and prospective studies.⁸ If inflammatory processes indeed play a part in the pathogenesis of intracranial arterial aneurysms, then we can expect the IL‐6 genotype to be similarly associated with aneurysmal disease. Our study examines this hypothesis.     

Polymorphisms of the NADPH oxidase P22PHOX gene in a Caucasian population with intracranial aneurysms

BACKGROUND: Vascular remodeling generated by reactive oxygen species contributes to aneurysm formation. The NADPH oxidase system is a major source of superoxide anion not only in phagocytes, but also in endothelial and vascular smooth muscle cells. Polymorphisms of p22phox, an essential component of the NADPH oxidase system, are found to be associated with atherosclerosis, while a recent study found a significant association between the 214C>T polymorphism and the occurrence of ischemic cerebrovascular disease. We conducted a case-control study to investigate the relationship of five polymorphisms of the P22PHOX gene and the occurrence of cerebral aneurysms. METHODS: The study population consisted of 113 patients with intracranial aneurysms and 53 control subjects. The 214C>T polymorphism was investigated by restriction fragment length polymorphism analysis, while polymorphisms 381T>C, 480G>A, 521C>T, and *24A>G were analyzed by direct sequencing of exon 6 and adjacent intronic sequences. RESULTS: The analysis of a primary study sample comprising 35 cases and 28 controls failed to show a significant association between any of the five polymorphisms and the occurrence of intracranial aneurysms using both allele frequencies and genotypes (all nominal p > 0.05). Although there was a deviation from Hardy-Weinberg equilibrium in cases at the 521C>T locus (nominal p < 0.05), this could not be confirmed in a second study sample of 78 patients. Haplotypes were constructed regarding three frequent polymorphisms (214C>T, 521C>T, and *24A>G); haplotype frequencies in cases and controls were not significantly different. CONCLUSION: Although polymorphisms of the P22PHOX gene located in the coding region and the 3'-untranslated region were reported to be associated with atherosclerosis and cerebrovascular disease, our data provide evidence that there is no association between these polymorphisms and the occurrence of cerebral aneurysms in Caucasians.