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.     

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     

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.     

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     

Angiotensin-converting enzyme I/D gene polymorphism and risk of multiple sclerosis

OBJECTIVES: Angiotensin-converting enzyme (ACE) activity is increased in blood and cerebrospinal fluid of patients with multiple sclerosis (MS). In addition, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the blockade of ACE suppresses the disease itself. To analyze the genetic association of the ACE gene with MS, we examined ACE gene insertion/deletion (I/D) polymorphism in MS patients. MATERIALS AND METHODS: A total of 313 MS patients from Slovenia and Croatia and 376 healthy controls were genotyped by polymerase chain reaction method. RESULTS: We found statistically significant differences in the distribution of ACE I/D allele frequencies (P < 0.01) and genotypes (P < 0.04) in male patients. ACE DD genotype was associated with MS in men at an odds ratio of 1.86 (95% CI 1.09-3.19, P = 0.02). CONCLUSIONS: DD genotype of ACE gene might contribute to a higher risk of developing MS in men.     

The I/D polymorphism of the ACE1 gene is not associated with ischaemic stroke in Spanish individuals

Background: The angiotensin‐converting enzyme 1 (ACE1) gene has been extensively studied in stroke, yet generating conflicting results. The goal of our study was thus to clarify the influence of the ACE1 on the risk of suffering an ischaemic stroke (IS). Methods: We genotyped the rs4341 (in linkage disequilibrium with the I/D polymorphism) of the ACE1 gene in 531 patients with IS and 549 healthy controls, and the rs1799752 (I/D polymorphism) in a subset of 68 patients with IS and 27 controls. We also performed functional studies by measuring serum ACE protein levels and enzymatic activity in 27 controls, 68 patients with IS at baseline and 35 patients with IS 24 h after onset of stroke symptoms. Results: There was no association of the ACE1 variant with IS, although it affected ACE protein levels (P = 0.001). Indeed, patients with IS showed lower ACE levels than controls in the acute phase (115.9 ± 38.9 vs. 174.1 ± 56.1 ng/ml, P < 0.001), but not in the chronic phase (168.2 ± 51.2, P = 0.673), and ACE protein levels did not differ between IS etiologies. Similar results were found for ACE activity. Conclusions: The D allele of the ACE1 I/D and ACE protein levels was not associated with a higher risk of IS in Spanish individuals.     

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.     

Cognitive and functional impairments in ischemic stroke patients with concurrent small vessel and large artery disease

Background and purpose

Concurrent small vessel, intracranial and extracranial large artery disease (SLAD) is common in Asian but its impact on cognitive and functional outcomes is unclear. We aimed to evaluate the clinical, cognitive and functional outcomes in ischemic stroke patients with SLAD.

Methods

Chinese ischemic stroke patients with diffuse white matter lesions (WMLs) were recruited as part of the VITATOPS Trial. They were studied with MRI and MRA of brain. Various neuropsychiatric batteries were used to assess the cognitive functions.

Results

Totally 97 patients with acute ischemic stroke and diffuse WMLs were included, of whom 44 (45%) had SLAD. Patients with SLAD had lower Mini Mental State Examination (MMSE) when compared with the patients without SLAD. They had more behavioral symptoms and caused more stress in caregivers as assessed by the Neuropsychiatric Inventory (NPI). Multivariate regression analysis showed SLAD contributed significantly to MMSE, NPI Patient (NPI P) and NPI Care Giver (NPI CG). Among 44 patients with SLAD, 30 (68%) had severe cognitive impairment. They were older and less educated. They had more diabetes and poorer performance in neuropsychiatric tests including Mattis Dementia Rating Scale Initiation/Perseveration subset (MDRS I/P) and Clinical Dementia Rating (CDR). They also had poorer functional outcomes as assessed by Barthel Index (BI) and Instrumental activities of daily living (IADL).

Conclusions

This was the first MRA-based study to take into consideration the clinical, cognitive and functional outcomes in ischemic stroke patients with SLAD. Patients with SLAD had poorer cognitive and functional outcomes when compared to patients without SLAD.     

新疆地区维、汉族缺血性脑卒中患者磷酸二酯酶4D基因单核苷酸多态性的研究

目的探讨新疆地区维、汉族缺血性脑卒中患者磷酸二酯酶4D(PDE4D)基因87位点的单核苷酸多态性(SNP)。方法采用PCR限制性片段长度多态性(PCR-RFLP)和基因测序方法检测226例缺血性脑卒中患者(病例组,维族110例,汉族116例)和220例无神经系统疾病的患者(对照组,维族102例,汉族118例)PDE4D基因87位点的多态性。对各组基因型分布和等位基因频率进行比较。结果病例组与对照组PDE4D基因87位点的基因型分布比较,差异无统计学意义;病例组PDE4D基因87位点C等位基因频率明显高于对照组(P<0.05)。病例组维族亚组PDE4D基因87位点CC型的比率及C等位基因频率明显高于对照组维族亚组(均P<0.05);病例组汉族亚组PDE4D基因87位点CC型的比率及C等位基因频率明显高于对照组汉族亚组(均P<0.05)。病例组中,维族亚组与汉族亚组PDE4D基因87位点的基因型分布及等位基因频率比较,差异无统计学意义;对照组中,维族亚组与汉族亚组PDE4D基因87位点的基因型分布及等位基因频率比较,差异亦无统计学意义。结论 PDE4D基因87位点C等位基因频率增高可能增加缺血性脑卒中发生的风险,此风险在新疆地区维、汉族人群中没有差异。     

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     

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.     

Association of phosphodiesterase 4D gene G0 haplotype and ischaemic stroke in a Greek population

We have examined the association of phosphodiesterase 4D ( PDE4D ) single nucleotide polymorphism (SNP45) and microsatellite marker AC008818-1 with ischaemic stroke, in an independent cohort of Greek patients and control individuals with no clinical manifestations of vascular disease. Significantly different distributions were observed with respect to the AC008818-1 alleles, with allele 148 associating with an increased risk of stroke incidence, and allele 144 with a protective effect. In addition, the haplotype defined by allele 148 and G allele of SNP45 was found to be significantly increased in patients even though no statistically significant differences emerged with respect to SNP45 alone. The previously established association of a PDE4D gene haplotype with ischaemic stroke in a population from Iceland was independently confirmed in our Greek population, suggesting that PDE4D may be involved in the aetiology and pathogenesis of stroke.     

Effects of cerebral small vessel disease on the outcome of patients with ischemic stroke caused by large artery atherosclerosis

Objective: Cerebral small vessel disease (CSVD) describes a syndrome of neuroimaging, pathological, and associated clinical features caused by small intracranial vascular lesions, which commonly coexists with large artery atherosclerosis (LAA) and has been identified as a major cause of motor impairment over time. In this review, we aim to summarize the relationship between CSVD and LAA, and discuss the effects of CSVD on the clinical outcome of patients with ischemic stroke caused by LAA.

Methods: We searched and scanned all the literature with the keyword cerebral small vessel disease, cerebral microbleeds, white matter hyperintensity, silent lacunar infarcts, enlarged perivascular spaces and stroke in the database of Pubmed and MEDLINE (from inception to 1 February 2015).

Results: Various imaging phenotypes of CSVDs have different influences on the clinical outcome of patients with LAA stroke. The total brain burden of CSVD can represent the cumulative effects of different MRI features of CSVD, which has predictive value for recurrent stroke after ischemic stroke. Better quantification of the total brain burden of CSVD may help stratify patients more effectively in clinical practice.

Discussion: CSVD can significantly influence the clinical outcome of stroke in patients with cerebral infarction caused by LAA, and the methods to capture whole brain CSVD burden cross the spectrum of changes in CSVD imaging features may be useful for patient stratification in clinical trials. Further studies should be performed to validate the relationship between CSVD related brain damage and LAA stroke.     

磷酸二酯酶4D基因与缺血性脑卒中的研究进展

磷酸二酯酶4D（PDE4D）在人体组织中广泛分布,其活性受环腺苷酸（cAMP）依赖的蛋白激酶（PKA）和细胞外信号调节激酶（ERK）调节。PDE4D基因包含1．6Mb,含24个外显子,编码9种蛋白质亚型和至少7个启动子。磷酸二酯酶4D降解cAMP,通过改变cAMP活性,促进动脉粥样硬化形成从而引起缺血性脑卒中发生。PDE4D基因多态性研究,为防治缺血性脑卒中提供了一条重要途径。     

基质金属蛋白酶-9/C1562T基因多态性与缺血性脑卒中的关系

目的探讨基质金属蛋白酶-9(MMP-9)启动子基因C1562T多态性与缺血性脑卒中(IS)的关系。方法采用聚合酶链式反应-限制性片段长度多态性分析(PCR-RFLP)法检测114例IS患者(IS组)及80名正常对照者(NC组)MMP-9/C1562T基因型和等位基因频率,分析其与IS发病的相关性。结果IS组与NC组间MMP-9/C1562T基因型及等位基因频率差异无统计学意义(P>0.05)。结论MMP-9/C1562T多态性可能与IS的发病无关。     

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.