Angiotensin converting enzyme (I/D) gene polymorphism contributes to ischemic stroke risk in Caucasian individuals: a meta-analysis based on 22 case-control studies

Background: Stroke is a multifactorial disease in which genetic factors play an important role. Previous studies associated angiotensin converting enzyme (ACE) (insertion/deletion, I/D) gene polymorphism with ischemic stroke risk in Caucasian individuals reported conflicting results. The purpose of this study was to evaluate the association between ACE (I/D) gene polymorphism and ischemic stroke risk by a meta-analysis. Methods: The related studies were searched in MEDLINE, EMBASE and HuGEnet databases. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for ischemic stroke risk associated with this polymorphism were estimated using fixed-effect or random-effects model. Twenty-two studies (5528/5081 cases/controls) were eligible in our meta-analysis. Results: Overall, statistical associations of the ACE (I/D) polymorphism with ischemic stroke risk were found in dominant model (DD + ID versus II) : OR = 1.21, 95% CI = (1.06,1.38), P = 0.006, recessive model (DD versus ID + II): OR = 1.28, 95% CI = (1.05,1.55), P = 0.01, and homozygote comparison (DD versus II): OR = 1.37, 95% CI = (1.14,1.65), P = 0.001 for Caucasians. When stratifying according to stroke subtypes, there were similarly significant differences for small vessel disease in dominant model (DD + ID versus II) : OR = 1.44, 95% CI = (1.01,2.05), P = 0.04, recessive model (DD versus ID + II): OR = 1.30,95% CI = (1.09,1.55), P = 0.004, and homozygote comparison (DD versus II): OR = 1.44, 95% CI = (1.15,1.80), P = 0.001. Conclusion: This analysis suggests that the ACE (I/D) polymorphism may be a risk factor for ischemic stroke, genotype DD of ACE could increase the risk of ischemic stroke in Caucasians. Subgroup analyses indicate that stroke subtypes may be a genetic risk factor of ischemic stroke, and there might be a greater genetic liability with small vessel disease.     

血管紧张素转换酶基因多态性与高血压并脑梗死的关系

目的：探讨中国人中血管紧张素转换酶（ＡＣＥ）基因插入／缺失（Ｉ／Ｄ）与脑梗死的关系。方法：原发性高血压患者８９例,其中并发脑梗死４１例,正常对照组３０例,应用ＰＣＲ技术检测ＡＣＥ基因１６内含子的Ｉ／Ｄ多态性片段可分为三种基因型：纯合子缺失型（ＤＤ）、纯合子插入型（Ⅱ）,杂合子型（ＩＤ）。结果：显示,高血压并发脑梗死患者的Ｄ等位基因频率（０．６４）高于单纯ＥＨ（０．４２）和正常对照组（０．４５）。结     

ACE I/D polymorphism in Korean patients with ischemic stroke and silent brain infarction

Objectives –  Angiotensin-converting enzyme ( ACE ) polymorphism may play a role in stroke and silent brain infarction (SBI) susceptibility, but the results among the populations studied to date have not been consistent. Thus, we investigated the association between ACE genotypes and ischemic stroke and SBI in Korean patients.
Subjects and methods –  DNA samples from 237 stroke patients, 264 SBI patients and 234 age-matched controls were amplified using polymerase chain reaction to detect the ACE ins/del (I/D) polymorphism. Genotype was determined by the presence of a 490-bp band ( I allele) or a 190-bp band ( D allele) in agarose gel electrophoresis.
Results –  Odds ratios of the I/D and D/D genotypes and the overall (I/D + D/D) for the I/I genotype were significantly different between stroke patients and normal controls. However, there was no significant difference between patients with SBI and controls.
Conclusions –  This study is the first report of a significant association between ACE polymorphism and ischemic stroke in the Asian population. Although no consistent associations have been found between ACE polymorphism and stroke in the populations studied to date, the ACE polymorphism may be a genetic determinant of ischemic stroke, at least in Korean patients.     

The D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is associated with worse functional outcome of ischaemic stroke

Purpose: Insertion/deletion polymorphism in ACE gene (ACE I/D) is known to be associated with the occurrence of ischaemic stroke through its effect on pathogenesis of atherosclerosis and hypertension. This study was aimed to examine the association between this polymorphism with functional outcome of ischaemic stroke.

Method: This was a cross-sectional study. The subjects were patients with ischaemic stroke in a reference hospital in Yogyakarta, Indonesia. Data on demographic characteristics, stroke risk factors, comorbidities and stroke severity were assessed on admission. The functional outcome, Barthel index (BI), was assessed when the patients were discharged from the hospital. ACE I/D genotypes of the patients were identified by polymerase chain reaction (PCR).

Result: In total, 61 patients were included. Of these, 38 patients (62.3%) had II polymorphism, 22 patients (36.1%) had ID polymorphism and 1 patient (1.6%) had DD polymorphism in the ACE gene. There were significant differences in the functional outcomes between patients without D allele (II polymorphisms) and patients with D allele (ID and DD polymorphism) (mean BI on discharge: 75 ± 23.57 and 60.65 ± 27.15, respectively; p = 0.034). Multiple linear regression model showed that the availability of D allele is an independent variable negatively associated with functional outcome as assessed by BI (β = ?0.232, p = 0.024).

Conclusion: This study showed that the D allele in ACE I/D polymorphism is associated with worse functional outcomes. This highlights the possibility of further research to improve functional outcomes of ischaemic stroke by inhibiting the ACE system.     

ACE I/D polymorphism in different etiologies of ischemic stroke

OBJECTIVES: Data concerning an association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and ischemic stroke (IS) remain inconsistent. Results of some studies suggest that DD genotype may be a risk factor for small vessel disease (SVD) stroke. Here, we investigated whether this polymorphism is associated with IS of different etiologies in a Polish population. SUBJECTS AND METHODS: Ischemic stroke etiology was established according to the TOAST criteria. We studied 92 stroke patients with large vessel disease and their 184 matched controls; 96 stroke patients with SVD and 192 controls; 180 patients with cardioembolic stroke (CE) and 180 controls. ACE I/D polymorphism was determined using the polymerase chain reaction method. RESULTS: The distribution of ACE genotypes and alleles was essentially the same in all analyzed IS subtypes and their matched controls. CONCLUSIONS: We failed to find an association between ACE polymorphism and etiological subtypes of IS in a Polish population.     

Polymorphism of the gene of angiotensin converting enzyme: lack of association with mood disorder

Summary. The insertion/deletion polymorphism of the gene of angiotensin-converting enzyme (ACE) was investigated in a case-control study including 169 patients with suffering from either bipolar disorder type I or unipolar recurrent major depression (DSM-IV) and 169 healthy controls. No significant association was found with bipolar disorder type I or unipolar recurrent depression and the polymorphism of the ACE gene. A previously reported genetic association (Arinami et al., 1996) was not confirmed by the present study. Received October 29, 1999; accepted April 6, 2000     

脑梗死患者血管紧张素转换酶基因多态性的研究

目的 研究肾素－血管紧张素转换酶（ＡＣＥ）基因多态性与脑梗死的关系。方法 通过ＰＣＥ方法研究７６例脑梗死患者（其中高血压患者５１例）及３０例健康对照者的ＡＣＥ基因。结果 脑梗死组ＤＤ／ＩＩ基因型显著增高／降低（Ｐ〈０．０５,Ｐ〈０．０１）,尤其伴设备在压的脑梗死患者这种趋势更为明显。结论 ＡＣＥ基因多态性和高血压脑梗死患者有关联性,ＤＤ基因型提示可能与高血压患者发生脑梗死有关,而ＩＩ型为保护型基因     

Evaluation of the roles of the Leiden V mutation and ACE I/D polymorphism in subtypes of ischaemic stroke

Objective The Leiden V mutation, which causes activated protein C resistance and thrombophilia, has been found to be a risk factor for venous thrombosis. The angiotensin converting enzyme (ACE) D allele indirectly exerts an unfavourable effect on the vasoregulatory system. In this study, the frequency of these mutations was analysed in different subtypes of ischaemic stroke. Method and material According to the clinical and radiological features 664 Hungarian patients who had suffered acute ischaemic stroke were divided into 3 subtypes: small and large vessel infarcts and a mixed type. In all 664 patients, the Leiden V mutation and ACE I/D polymorphism were examined by means of the PCR technique. The frequencies of the different genotypes for the Leiden V mutation and ACE I/D polymorphism in the 3 subgroups of stroke were compared with 199 stroke-free control subjects whose MRI findings were normal. Results No significant associations were found between the overall group of cerebral infarctions and the Leiden V, ACE I/D and ACE D/D genotypes. The ACE D/D genotype was significantly more common in the patients with small deep infarcts (40.3 %; p < 0.0005; OR 2.31, 95 % CI 1.49–3.57) than in the control group (22.6 %). The Leiden V mutation was significantly more common in patients with large infarcts (13.6 %; p < 0.025; OR 2.25, CI 1.16–4.34) than in the stroke-free control subjects (6.5 %). Conclusions The ACE D/D genotype possibly contributes to the occurrence of small-vessel infarcts rather than large vessel infarcts. The Leiden V mutation might predispose to large brain infarcts. Neither the Leiden V factor nor the ACE D/D genotype has been proved to be a risk factor for ischaemic stroke as a whole. Received: 22 June 2000 / Received in revised form: 5 February 2001 / Accepted: 3 March 2001     

高原地区藏族ACE基因I/D多态性与脑出血的关系研究

目的探讨血管紧张素转化酶(ACE)基因插入/缺失(I/D)多态性与高原地区世居藏族脑出血的相关性。方法收集青海地区高原世居藏族脑出血患者52例(男27例,女25例)为病例组,与之年龄、性别、居住地相匹配的同期体检的世居健康藏族51例(男28例,女23例)为对照组,收集一般资料。利用聚合酶链式反应(PCR)检测所有样本的ACE基因I/D多态性。结果病例组ACE基因型:DD型9例(17.31%),II型21例(40.38%),ID型22例(42.31%);等位基因频率:D等位基因38.46%,I等位基因61.54%;对照组ACE基因型:DD型10例(19.61%),II型19例(37.26%),ID型22例(43.13%);等位基因频率:D等位基因41.18%,I等位基因58.82%。两组间基因型、等位基因比较无显著性差异(基因型χ~2为0.14,等位基因χ~2为0.16,P0.05)。结论ACE基因I/D多态性与青海高原地区藏族脑出血无相关性,ACE基因I/D多态性可能不是高原世居藏族人群脑出血的遗传易感因素。     

血管紧张素转换酶I/D和血管紧张素Ⅱ受体-1A1166C基因多态性与脑梗死的关系

目的探讨血管紧张素转换酶(ACE)基因I/D多态性和血管紧张素Ⅱ受体-1(AT1R)A1166C基因多态性与脑梗死(CI)的关系。方法应用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)技术检测88例CI患者和90名健康对照者的ACE和AT1R基因型和等位基因频率,并进行比较。结果CI组AT1R基因AC基因型频率为31.8%,C等位基因频率15.9%,明显高于正常对照组(11.1%,5.6%)(均P<0.05);同时携带AT1R基因AC基因型和ACE基因DD基因型的个体CI的患病危险度为4.070(P<0.05);同时携带AT1R基因AC基因型和ACE基因ID基因型的个体CI的患病危险度为2.057(P>0.05)。结论AT1R基因A1166C基因多态性可能是CI发病的遗传因素;与ACE基因DD基因型间具有协同致CI作用。     

The Sma I polymorphism in the von Willebrand factor gene associated with acute ischemic stroke.

The von Willebrand factor (vWF) is a highly multimerized glycoprotein that promotes platelet adhesion and aggregation at a high shear rate, and also acts as a carrier of coagulation factor VIII. vWF has been identified as a risk factor for recurrent myocardial infarction in the general population. It has been reported that two polymorphisms of vWF gene promoter and the Thr789Ala polymorphism in vWF gene are associated with arterial thrombosis. The Sma I polymorphism is located in intron 2 of vWF gene. The relevance of this polymorphism to thrombotic disease was investigated by genotypic identification in two case–control studies: 107 patients with acute ischemic stroke, 49 patients with acute myocardial infarction (AMI), and 113 health controls age- and race-matched for each patient. Twenty-eight (26.2%) of the 107 patients with acute ischemic stroke, 8 (16.3%) of 49 patients with AMI, and 11 (9.7%) of 113 controls were found to be homozygous for CC genotype, respectively. The prevalence of the CC genotype in acute ischemic stroke was significantly higher than that of the normal controls (odds ratio [OR]=3.29, 95% confidence interval [CI]=1.54–7.01, .01>P>.001). However, the prevalence of the CC genotype in AMI was not significantly different from that of the normal controls (OR=1.81, 95% CI=0.68–4.82, .30>P>.20). Plasma vWF:Ag was also determined by enzyme-linked immunosorbent assay (ELISA) on the frozen plasma of 122 subjects. The mean plasma vWF:Ag levels of the controls, patients with acute ischemic stroke, and AMI were 0.468, 0.584, and 0.783 U/ml, respectively. The mean level of plasma vWF:Ag did not differ significantly between controls and patients with acute ischemic stroke (P=.195), but had significantly difference between controls and patients with AMI (P=.001). No association was found between the Sma I polymorphism and vWF plasma levels in controls, patients with acute ischemic stroke, or the AMI group (one-way ANOVA, P=.323, P=.315, P=.96). Results show that the Sma I polymorphism is strongly associated with increased risk of acute ischemic stroke, however, no association was observed between this polymorphism and AMI. This polymorphism of vWF may represent a newly identified risk factor for acute ischemic stroke in Chinese. Whether it is the real functional variant associated with acute ischemic stroke remains to be elucidated.     

血管紧张素转换酶基因多态性与血管性痴呆发病关系的研究

目的　探讨血管紧张素转换酶(ACE)基因多态性与血管性痴呆(VD)的相关性。方法　采用 聚合酶链反应(PCR)技术,检测94例VD患者(VD组)、60例原发性高血压患者(EH组)及60名健康成人 (NC组)的ACE基因型及等位基因的频率,并进行比较分析。结果　有关DD型及D等位基因频率组间比较 结果:(1)VD组比NC组明显增高(均P<0.01)。(2)脑卒中后VD患者高于非脑卒中后VD患者(由于病例 数相差太大,未进行统计学分析)。(3)VD伴EH者高于VD不伴EH者(均P<0.05)。(4)VD的程度与 ACE基因型的分布无关。结论　ACE基因I/D多态性与VD有一定的相关性;DD型及D等位基因可能是 VD的危险因素。     

The C242T polymorphism of the gene encoding cytochrome b-245 alpha is not associated with paediatric ischaemic stroke: family-based and case-control study

Background and purposeReactive oxygen species play an important role in the physiology and pathology of cerebral arteries, including ischaemic stroke. The cytochrome b-245 alpha gene (CYBA) encodes cytochrome b-245 alpha light chain (p22phox peptide), a critical element of NAD(P)H oxidases, the most important source of superoxide anion in the cerebral arteries. To search for genetic factors associated with paediatric ischaemic stroke, the possible association between CYBA gene C242T polymorphism and the disease was evaluated.Material and methodsThe study group consisted of 238 individuals: children with ischaemic stroke (n = 70), their biological parents (n = 118) and children without any symptoms of stroke (n = 50). The C242T polymorphism was genotyped using polymerase chain reaction – restriction fragment length methodology. To evaluate the possible association between polymorphism and stroke, the transmission disequilibrium test and the case-control method were applied.ResultsThe C242 allele was transmitted more frequently than 242T (62.2% vs. 37.8%) but observed frequencies did not differ significantly from expected (p = 0.10). There were also no significant differences in allele and genotype distribution between patients and control subjects (patients: CC – 50.0%, CT – 38.6%, TT – 11.4% vs. controls: CC – 52.0%, CT – 36.0%, TT – 12.0%).ConclusionsThe study did not show that the C242T polymorphism of the CYBA gene is a risk factor of ischaemic stroke in children.     

Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans

Genes associated with muscle metabolism and physical endurance were evaluated for variants that may contribute to the etiology of medically unexplained severe and chronic fatigue. Subjects included 49 Gulf War veterans and 61 nonveterans with chronic fatigue syndrome (CFS) or idiopathic chronic fatigue (ICF) and 30 veterans and 45 nonveterans who served as healthy controls. Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. The I allele frequency was decreased in affected versus unaffected veterans (0.15 versus 0.48; odds ratio [OR], 5.08; 95% confidence interval [CI], 1.97-13.35; P < 0.0001). Correspondingly, the II genotype was decreased fourfold in affected veterans (0.08 versus 0.35; OR = 5.87; 95% CI: 1.21-28.36; P = 0.02), and the DD genotype was increased twofold (0.78 versus 0.39; OR, 5.4; 95% CI, 1.6-18.4; P = 0.007). Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype (OR, 8.30; 95% CI, 1.50-56.09; P = 0.009).     

蒙古族腔隙性脑梗死患者的ACE基因多态性研究

目的探讨血管紧张素转换酶(ACE)基因与蒙古族腔隙性脑梗死(LI)的关系和ACE基因I/D多态性的遗传规律.方法采用聚合酶链反应(PCR)扩增方法检测33例LI患者和30例健康人的ACE基因型,并对两者ACE基因I/D多态性进行对比分析.结果患者ACE基因DD基因型及D等位基因频率为(0.3,0.47)明显高于对照组(0.1,0.25),二者相比有显著性差异(P＜0.05).结论ACE基因插入(I)/缺失(D)多态性与蒙古族LI患者有关,ACE基因DD基因型或D等位基因可能是蒙古族LI患者的遗传学基础之一     

血管紧张素转换酶基因多态性与脑血管病的关系

目的　探讨血管紧张素转换酶 (ACE)基因多态性与脑血管病的关系。方法　应用聚合酶链反应 (PCR)方法对 10 0例脑血管病患者 (脑血管病组 )和 10 0名健康体检者 (对照组 )进行ACE基因检测及基因多态性分析。结果　DD基因型频率脑出血组 (34 4 % )明显高于对照组 (16 .0 % ) (P <0 0 5 ) ;脑血管病合并原发性高血压组明显高于不合并原发性高血压组 (P <0 0 5 ) ;合并血糖异常组明显高于血糖正常组 (P <0 0 5 ) ;且伴血脂异常组DD基因型频率和D等位基因频率明显高于血脂正常组 (P <0 0 5 )。结论　DD基因型是脑出血患者的高危因素 ;DD基因型和D等位基因可能与脑血管病的高危因素如血糖、胆固醇、高密度脂蛋白水平等有一定的关系     

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.     

脑梗死疾病与血管紧张素转换酶基因多态性的相关性研究

目的 研究血管紧张素转换酶(ACE)基因、血管紧张素Ⅱ受体Ⅰ型(ATⅠR)基因多态性和多种危险因素与脑梗死疾病的相关性。方法 采用整群抽样的方法选取唐山开滦矿业集团职工1351人。所有样本均清晨空腹抽取静脉血测定其ACE、ATⅠR基因型及相关生化指标，并进行体检和问卷调查，然后依据头部CT或MRI结果将之分为脑梗死组和对照组。结果 ACE基因各基因受在脑梗死组和对照组的频率分布及各基因型人群中脑梗死患病率无明显差异，ATⅠR基因AA基因型频率分布在脑梗死组高于对照组，且AA型人群脑梗死患病率高于其它基因型，但两种基因各联合基因型人群中脑梗死患病率无差异。在与脑梗死有关的各种危险因素存在条件下，仅不吸烟人群和有高血压患者群中脑梗死组ATⅠR基因AA基因型频率分布高于对照组．Logistic回归发现脑梗死与ATⅠR基因多态性和性别有明显相关性。结论 在具有高血压病的ATⅠR的AA基因型人群发生脑梗死的危险性明显增加，说明脑梗死的发病可能是“基因与环境”因素共同作用的结果。