Apolipoprotein A5 gene C56G variant confers risk for the development of large-vessel associated ischemic stroke

OBJECTIVES: Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of stroke. The aim of our study was to investigate the possible association between the C56G variant of the apolipoprotein A5 (APOA5) gene and ischemic stroke. METHODS: PCR-RFLP assays were performed to detect the C56G alleles in 403 patients with classified stroke types and 171 controls. RESULTS: Triglyceride levels of subjects carrying 56G allele were elevated compared to the subjects with 56C allele in all stroke subgroups and in the controls. The serum total cholesterol levels did not differ between subjects with C or G alleles in each group. An accumulation of APOA5 56G allele was observed in the large-vessel associated stroke group compared to the healthy controls (10.9 vs. 5.6 %; p < 0.05), while its prevalence did not increase in any other stroke subgroups. Multivariate logistic regression analysis adjusted for differences in age, gender, BMI, serum total cholesterol levels, ischemic heart disease, hypertension, diabetes mellitus, smoking and drinking habits revealed that the APOA5 56G allele represents a susceptibility factor for large-vessel associated stroke (OR = 2.132 at 95 % CI; p < 0.05). CONCLUSION: The data presented here suggest that the 56G allele can confer risk exclusively for development of large-vessel associated stroke. Thereby, the 56G allele differs from the APOA5 T-1131C allelic variant, which has been previously identified as a risk factor for all subgroups of the stroke disease.     

Association of the 5-HT2A receptor gene polymorphism 102 T/C with ischemic stroke

Serotonin (5-HT) has been implicated in a number of cardiovascular disorders due to its ability to induce vascular contraction and platelet aggregation through activation of the 5-HT2 receptor family. In this study, we investigated the association of stroke in a Scandinavian population with two common polymorphisms in the 5-HT2A receptor gene. The two polymorphisms under investigation, namely the 102T/C and the −1438A/G variations of the 5-HT2A receptor gene, were examined in a case control association study involving 99 stroke patients and a comparable number of controls. Among patients, the prevalence of the homozygous 102T/T genotype was significantly higher than in controls (28.3% vs 13.5%; p<0.01). The allelic frequency of 102T carriers was also significantly higher in stroke patients than in controls (p=0.002, OR=1.88, 95%CI, 1.27–2.80). The association between the 102T allele and stroke was significant in both males and females. There was no association between stroke and the −1438A/G polymorphism. Taken together, this study indicates that the 102T/C polymorphism in the 5-HT2A receptor gene could be an independent risk factor for developing stroke.     

Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke

The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. A total of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p<0.005, OR, 2.33; 95% CI, 1.46–3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9–6.24; p<0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88–7.16; p<0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.     

湖南汉族人群ApoA5基因T-1131C多态性分布及其与脑梗死的关系

目的探讨载脂蛋白A5(ApoA5)基因T-1131C多态位点在湖南地区汉族人群中的分布及其与脑梗死和血脂的关系。方法我们收集200例正常对照组和153例脑梗死患者血标本,用聚合酶链反应-限制性片段长度多态性分析法检测ApoA5基因T-1131C多态性在脑梗死组和正常对照组的基因频率。同时检测研究对象的血脂和脂蛋白水平。结果中国湖南地区人群存在ApoA5基因T1131C多态性,在正常对照组中T/C等位基因频率是0.717/0.283,脑梗死组ApoA5T-1131C等位基因频率显著低于正常对照组,差异有统计学意义(P<0.05),C等位基因携带者的TG,LDL水平显著高于对照组,差异有统计学意义(P<0.05)。结论ApoA5基因多态性可能参与血脂代谢,并与中国湖南汉族人群脑梗死的发生相关。     

Association of the A1298C polymorphism in MTHFR gene with ischemic stroke

A meta-analysis was performed to assess the association between the methylenetetrahydrofolate reductase (MTHFR) A1298C genetic polymorphism and ischemic stroke. A comprehensive search was conducted to identify all case–control or cohort studies. The fixed or random effect pooled measure was selected based on the homogeneity between studies, as assessed by I². Meta-regression was used to explore the potential sources of between-study heterogeneity. Publication bias was estimated using Egger’s linear regression test. Thirteen case–control studies corresponded to the inclusion criteria comprising 2133 patients and 2572 controls which were included in the present meta-analysis. After excluding articles that deviated from Hardy–Weinberg equilibrium in controls and the key contributors to between-study heterogeneity, significant associations between MTHFR A1298C genetic polymorphism and risk of ischemic stroke were observed in dominant (odds ratio [OR] 1.227, 95% confidence interval [CI] 1.062–1.416) and codominant (OR 1.138, 95% CI 1.007–1.286) inheritance models. Moreover, in the subgroup analysis based on region (Asia and Europe), significant associations were observed in most genetic models in Asia but not in Europe. This meta-analysis suggests that MTHFR A1298C genetic polymorphism is associated with increased risk of ischemic stroke, and the C allele may be an important risk factor for ischemic stroke.     

G501C polymorphism of oxidized LDL receptor gene (OLR1) and ischemic stroke

The human lectin-like oxidized low-density lipoprotein receptor 1 (OLR1/LOX-1) is the major endothelial scavenger receptor against oxidized low-density lipoprotein (Ox-LDL), which has been implicated in the pathogenesis of atherosclerosis. We investigated the G501C mutation in the OLR1 gene in 235 Japanese patients with ischemic cerebrovascular disease (CVD) and 274 age- and sex-matched healthy controls using single nucleotide primer extension analysis (SNuPe). There was no significant difference in the polymorphism between patients with ischemic CVD and controls (GC+CC versus GG, p=0.48). The C allele was not significantly different between the patients and controls (C versus G, p=0.91). Our results show that the OLR1 gene polymorphism has little effect on an increased risk for ischemic CVD in the Japanese population.     

中国人群ALOX5AP基因SG13S114A/T多态性与缺血性卒中相关性的Meta分析

目的对5-脂氧合酶激活蛋白(ALOX5AP)基因第1内含子SG13S114A/T多态性与缺血性卒中(IS)的关联性研究进行meta分析。方法通过文献检索2004～2009年发表的中国人ALOX5AP基因SG13S114A/T多态性与IS相关性的病例-对照研究,剔除不符合要求的文献;以基因型和等位基因频数的优势比(OR)值为统计量,以漏斗图和Egger法检验发表偏倚,根据同质性检验结果合并数据,采用Revman4.2版统计软件进行数据统计。结果 5篇文献符合条件纳入研究,入选文献无明显发表偏倚。同质性检验显示基因型(AA+AT)/TT的统计量χ2=1.00,P=0.91;等位基因频数A/T的统计量χ2=8.18,P=0.09,各研究间无异质性。数据合并结果显示,SG13S114A/T位点(AA+AT)/TT的OR值为1.22,95%CI为1.09～1.36,Z值为3.5,P<0.05;等位基因频数A/T的OR值为1.05,95%CI为0.96～1.14,Z值为1.09,P=0.28。结论 ALOX5AP基因SG13S114A/T多态性与中国人群IS具有相关性,AA基因型可能是IS的易感基因型。     

5-羟色胺1A受体基因C(-1019)G多态性与精神分裂症的关联分析

目的:探讨云南地区汉族人群中5-羟色胺1A(5-HT1A)受体基因C(-1019)G多态性与精神分裂症的关联,及其对症状组成、前额叶执行功能的可能影响. 方法:应用阳性与阴性症状量表(PANSS)、简明精神病评定量表(BPRS)、外显攻击量表(OAS)等评定患者症状,威斯康星卡片分类测验(WCST)评定精神分裂症和正常人前额叶执行功能.142例精神分裂症患者和84名正常对照分别用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型. 结果:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性在精神分裂症和正常人之间的各量表分差异有显著性(P=0.001).C(-1019)G多态性对PANSS中因子被动淡漠性社会退缩(N4)(P=0.010)、言语缺乏主动性和流畅性(N6)(P=0.004)、阴性症状总分(NT)(P=0.013)、紧张(G4)(P=0.005)、自发社交回避(G16)(P=0.013),以及BPRS中的因子4激活性(P=0.026)等条目得分的形成影响有显著性.C(-1019)G多态性与WCST各条目不相关. 结论:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性与精神分裂症显著相关,对精神分裂症症状组成可能起一定作用,但与WCST反映的前额叶执行功能状态并无显著相关.     

五羟色胺2C受体基因多态性与抗精神病药急性期治疗精神分裂症疗效关系初探

目的 研究五羟色胺2C受体(5HTR2C)基因启动子区功能多态性与首次治疗的精神分裂症患者精神症状严重程度及抗精神病药物(APS)急性期治疗疗效相关性。方法 采用PCR-RFLP方法分析109例首次治疗精神分裂症患者(男53例,女56例)5HTR2C基因启动区-759C/T单核酸置换多态性;临床用阳性和阴性症状量表(PANSS)评定患者治疗前后精神症状,分析单体型(男性)或暴因型(女性)和其他临床指标与治疗前PANSS分值和治疗后PANSS减分率的相关性。结果5HTR2C基因-759C/T基因型在女性患者组的分布频率符合H-W定律(P>0.05);-759T单体型(男性)或携带-759T的基因型(女性)在治疗显效组和治疗未显著进步组分布频率无显著性差异;单体型或基因型亚组的临床指标均无显著性差异;-759C/T对首次治疗精神分裂症患者PANSS分值无显著影响,但对治疗10周后PANSS总减分率和阴性症状减分率有显著影响。结论 5HTR2C基因启动子区-759C/T单核酸置换多态性在APS急性期治疗疗效中,可能主要影响对阴性症状的控制。     

No association of C-1019G promoter polymorphism of 5-HT1A receptor gene with migraine

It is well known that migraine has a strong genetic component, although the type and number of genes involved remains unclear. There is evidence to suggest that serotonin-related genes may be involved in the pathogenesis of migraine. To investigate whether the 5-HT1A receptor gene contributes to the risk of migraine we performed an association study of C-1019G promoter polymorphism of the gene in 102 migraineurs and 93 controls. Subjects were of Han Chinese origin. No significant differences in allele (P=0.82) or genotype frequencies (P=0.71) were seen in migraineurs compared with the controls. When migraine with aura, without aura, with family history, without family history were analyzed separately, the frequencies did not vary significantly. Our results suggest that C-1019G in 5-HT1A is not a major genetic risk factor for migraine.     

Integrin, alpha 2 gene C807T polymorphism and risk of ischemic stroke: a meta-analysis

INTRODUCTION: Platelet adhesion to fibrillar collagen via the membrane glycoprotein (GP) Ia/IIa (alpha2beta1), is a crucial event in the pathogenesis of arterial occlusive disorders. The C807T single nucleotide polymorphism of the integrin, alpha 2 (ITGA2) gene has been shown to correlate with the platelet GPIa/IIa density. Consequently, subjects with the 807T allele, who express the highest receptor density, might have an increased potential of platelet adhesion and, hence an increased risk of cerebrovascular disease. However, the research findings remain controversial. MATERIALS AND METHODS: A comprehensive electronic search was carried out up until November 2005 and 7 independent studies with a maximum of 774 cases and 1074 controls were analyzed using random effects models. RESULTS: The pooled frequency of the T allele was 36.33% in cases and 37.01% in controls. The T versus the C allele contrast gave an OR of 1.11 (95% confidence interval=0.827-1.499). All the other comparisons failed to show any significant result. Age, sex, and cardiovascular risk factors were included as covariates into a meta-regression model without a significant finding. CONCLUSIONS: This meta-analysis do not support an association between the C807T polymorphism of ITGA2 gene and stroke, but given the significant between study heterogeneity and the small number of studies, the summary effect should be interpreted carefully.     

中国人PDE4D基因(83T/C)多态性与缺血性脑卒中相关性的Meta分析

目的 综合评价中国人磷酸二酯酶4D(phosphodiesterase 4D,PDE4D)基因83T/C多态性与缺血性脑卒中发病的关系.方法 利用Meta分析方法对国内外公开发表的有关中国人PDE4D基因83T/C多态性与缺血性脑卒中关系的研究文献进行综合定量分析.结果 有6篇文献符合条件纳入研究,累积病例共1899例,累积对照组共2431例.Meta分析显示,以TT基因型为参照,携带CC基因型个体发生缺血性脑卒中危险性的OR值为1.53,95%,CI为1.22～1.9l,Z=3.69,P＜0.05;携带CC或CT基因型的个体发生缺血性脑卒中的危险性的OR值为1.34,95%,C I为1.18～1.53,Z=4.48,P＜0.05;等位基因频数C/T的OR值为1.28,95%,CI为1.15～1.41,Z=4.75,P＜0.05.结论 PDE4D基因83T/C多态性与中国人缺血性脑卒中的发病具有相关性.     

Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both stroke subtypes in patients with methylenetetrahydrofolate reductase gene polymorphisms. Therefore, we examined whether the C677T and A1298C polymorphisms of MTHFR gene are genetic risk factors for both ischemic and hemorrhagic stroke in a Turkish Caucasian population. In a case-control study, 120 total unrelated stroke patients (92 ischemic stroke, 28 hemorrhagic stroke), and 259 healthy controls were genotyped for C677T and A1298C polymorphisms of the MTHFR gene using a PCR-RFLP based-method. The MTHFR 1298C allele (chi(2)=8.589; P=0.014), C1298C genotype (OR=2.544; P=0.004), and C677C/C1298C compound genotype (OR=3.020; P=0.001) were associated with overall stroke. The MTHFR 1298C allele (chi(2)=11.166; P=0.004), C1298C genotype (OR=2.950; P=0.001), and C677C/C1298C compound genotype (OR=3.463, P=0.0001) were strongly associated with ischemic stroke. Interestingly however, the MTHFR 677T allele (chi(2)=6.033; P=0.049), T677T genotype (OR=3.120; P=0.014), and T677T/A1298A compound genotype (OR=4.211; P=0.002) were associated with hemorrhagic stroke. In conclusion, the C677T and A1298C polymorphisms of the MTHFR gene are genetic risk factors for hamorrhagic and ischemic stroke respectively, independent of other atherothrombotic risk factors.     

缺血性脑卒中及不同亚型与血浆脂蛋白相关磷脂酶A2水平及其基因I198T多态性的关系

目的 研究缺血性脑卒中(IS)及不同亚型与血浆脂蛋白相关磷脂酶A2(Lp-PLA2)水平及Lp-PLA2基因I198T多态性的关系.方法 228例IS患者按急性卒中Orgl 10172治疗试验(TOAST)分型分为大动脉粥样硬化性脑卒中(LAA)组(123例)、小动脉闭塞性脑卒中(SAO)组(71例)和心源性栓塞(CE)组(34例).采用酶联免疫吸附法(ELISA)测定血浆Lp-PLA2水平,应用PCR及基因直接测序法确定Lp-PLA2基因I198T位点的多态性;计算IS相对危险度.并与202名正常对照者比较.结果 IS组及其LAA亚组的血浆Lp-PLA2水平、Lp-PLA2基因I198T位点突变基因型、等位基因频率及其IS相对危险度均显著高于正常对照组(P ＜0.01～0.001);SAO和CE亚组以上指标与正常对照组的差异均无统计学意义.各组不同基因型之间血浆Lp-PLA2水平的差异无统计学意义.结论 IS及其LAA亚型患者的血浆Lp-PLA2水平明显升高,Lp-PLA2基因I198T多态性与LAA的发生有密切关系,而与SAO和CE的发生可能无关.     

酒依赖共病双相情感障碍患者冲动攻击行为与5-HTR1B基因多态性关联分析

目的探讨酒依赖共病双相情感障碍患者的冲动攻击行为与5-HTR1B rs6296基因多态性的关联,为酒依赖共病双相情感障碍患者冲动攻击行为导致病理生理改变机制的潜在遗传学差异的研究提供参考。方法采用病例对照研究,纳入符合《精神障碍诊断与统计手册(第4版)》(DSM-IV)酒依赖共病双相情感障碍诊断标准的患者230例,依据修订版外显攻击行为量表(MOAS)评分分为有冲动攻击行为组(n=128)和无冲动攻击性行为组(n=102)。通过PCR直接测序法对rs6296基因多态性进行测定,并分析5-HTR1B rs6296基因多态性与酒依赖共病双相情感障碍患者冲动攻击行为的关联性。结果酒依赖共病双相情感障碍患者有冲动攻击行为组与无冲动攻击行为组rs6296位点的等位基因频率分布差异无统计学意义(χ~2=2.135,P0.05);两组rs6296位点基因型分布差异无统计学意义(χ~2=2.771,P0.05)。结论酒依赖共病双相情感障碍患者冲动攻击行为与5-HTR1B rs6296基因多态性无关联。