Renin-angiotensin system gene polymorphism in Japanese stroke patients

doi:10.1016/S0531-5131(03)00006-2

International Congress Series

Volume 1252, June 2003, Pages 83-90

https://doi.org/10.1016/S0531-5131(03)00006-2 Get rights and content

Abstract

A role of deletion (D)/insertion (I) polymorphism in angiotensin converting enzyme (ACE) gene or A/C polymorphism in angiotensin II type 1 receptor (AT₁R) gene polymorphism on ischemic stroke or leukoaraiosis were assessed in 129 Japanese ischemic stroke patients and 27 normal control subjects. Ischemic stroke patients were divided into three groups, including lacunar, atherothrombotic and cardio-embolic infarction. Leukoaraiosis was assessed with the grade of periventricular high intensity (PVH) and deep white matter lesion (DWL). The D allele of ACE gene (ACE*D) increased by 2.57-fold the risk of lacunar infarction although ACE*D did not significantly increase the risk of atherothrombotic and cardio-embolic infarction. ACE*D also had a 2.82- and 2.95-fold increased risk of PVH and DWL, respectively. AT₁R polymorphism showed no significant effect on ischemic stroke and leukoaraiosis. ACE*D increased the risk of normotensive lacunar infarction significantly although other risks except current smoking showed no significant effect on normotensive lacunar infarction. The findings of this study suggested a role of ACE polymorphism on lacunar infarction independent of hypertension.

Introduction

The genetic basis of some metabolic and coagulation disorders predisposing to stroke is known, but the molecular basis of the genetic predisposition in the majority of stroke patients remains unknown. Angiotensin converting enzyme (ACE) is important in the production of angiotensin II and the catabolism of bradykinin, both peptides involved in the modulation of vascular tone and the proliferation of smooth muscle cells.

Genes that influence the renin-angiotensin system (RAS) are potentially etiologic candidates for causing hypertension and cardiovascular disease. A deletion (D)/insertion (I) polymorphism in intron 16 of the ACE gene was associated with the level of circulating enzyme [1], myocardial infarction, and stroke [2]. In the stroke patients, lacunar infarction is attenuated in the association with the DD genotype of ACE gene more than large vessel disease [3], [4]. In addition, recent studies suggested that the DD genotype of ACE was associated with leukoaraiosis in essential hypertensive patients [5]. Angiotensin II type 1 receptor (AT₁R) gene polymorphism was also associated with hypertension, myocardial infarction and cerebral infarction [6]. However, contrasting findings have also been reported by other studies [7]. This discrepancy may be due to the different background of the stroke subtype, frequency of hypertension, or heterogeneous ethnicity in the study population. We investigated the association of ACE and AT₁R gene polymorphism with each stroke subtype or leukoaraiosis in symptomatic stroke patients.

Section snippets

Subjects

Subjects were 129 sporadic stroke patients and 27 normal controls (N), who agreed to participate in this study. Clinical history of stroke and personal history were taken from all subjects. All subjects were evaluated by neurological examination, brain Magnetic Resonance Imaging (MRI), and Magnetic Resonance Angiography (MRA). The cervical carotid artery was examined by ultrasonography in each stroke patient. The subtype of stroke was divided into three groups; lacunar infarction group (L),

Method

Leukoaraiosis was evaluated using periventricular high signal (PVH) and deep white matter lesion (DWL), independently. PVH was classified by consensus as having (1) normal, (2) small caps or a pencil-thin lining, (3) smooth halo, or (4) irregular halo. DWL was classified as having (1) normal, (2) spotty high signal, (3) beginning of confluent, or (4) confluent.

Genomic DNA was extracted from peripheral blood lymphocytes, using a DNA extraction kit (Quiagen). The I/D polymorphism of the ACE gene

Patients profile

The patient's numbers of each stroke subtype were as follows: lacunar infarction group (L) (n=72), atherothrombotic infarction group (AT) (n=36), and cardio-embolic infarction group (CE) (n=21). Clinical profiles of each group are shown in Table 1. The mean age of each subgroup was not significantly different from the mean age of the N group. The percentage of males in the AT group was higher than in the N group. Hypertension in both L and AT groups was significantly more frequent than in the N

Discussion

In this study, ACE*D was only significant in a dominant model of inheritance for increasing by 2.57-fold the risk of lacunar infarction over the control group. In contrast, the dominant effect of ACE*D showed a 2.29- and 2.36-fold greater risk of stroke than the control group in the AT group and CE group, respectively, but these odds ratios were not significant. This discrepancy might be due to a relatively small number in AT and CE group stroke, but a previous study also showed an association

Acknowledgments

This study was supported by a Japanese Research Project, Grant-In-Aid for Scientific Research (11670635). The authors thank Mr. Masaaki Kimata and Mr. Makoto Tada for their technical assistance. The authors thank Dr. Kohtaro Ozasa for his kind advice about statistical analysis. The authors also thank all members of our department for sample collection from the patients.

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Cited by (13)

Association Between the Angiotensin-Converting Enzyme I/D Polymorphism and Risk of Cerebral Small Vessel Disease: a Meta-Analysis Based on 7186 Subjects
2021, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
The I/D polymorphism involves the presence/ absence of an Alu sequence of 287 pb in intron 16 of the gene, and I/D polymorphism is associated with many diseases, therefore, I/D polymorphism is the most widely studied SNP. Indeed, numerous case-control studies4,11–36 have investigated whether the ACE I/D polymorphism influences the risk of CSVD, but the results have been inconclusive and contradictory. Thus, we performed a comprehensive meta-analysis of all available evidence on these potential associations.
Cerebral small vessel disease (CSVD) causes a quarter of all strokes and is the most common pathology underlying vascular dementia. However, the mechanism of CSVD remains unclear. Numerous studies have investigated whether the angiotensin-converting enzyme (ACE) intersection/deletion (I/D) polymorphism influences the risk of CSVD, but the results are controversial.
We searched English and Chinese databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine the existence of genetic associations between the ACE I/D polymorphism and the risk of CSVD. All relevant studies were screened and meta-analyzed using Review Manager 5.4.
A total of 27 studies involving 7,186 subjects were identified for the meta-analysis. The results of five genetic models showed a significantly increased risk of CSVD (allelic, OR=1.30; recessive, OR=1.41; dominant, OR=1.34; homozygous, OR=1.55 and heterozygous OR=1.22) in the overall analysis. Furthermore, in subgroup analysis, increased CSVD risks were also observed in Asian and Caucasian populations. We also found no relationship between ACE I/D and leukoaraiosis (LA) in patients with lacunar infarction (LI).
The ACE I/D polymorphism was positively associated with CSVD in both populations. However, this polymorphism did not increase the risk of LA in LI patients.
Genetic determinants in ischaemic stroke subtypes: Seven year findings and a review
2015, Gene
Citation Excerpt :
Most noted difference of the stroke registry of NIMS (the study hospital) from western registries was the predominance of ILA rather than ELA of LAA. However, association with risk of lacunar infarction has been reported in a Japanese population with no effect in atherothrombotic and cardioembolic infarction (Mizuno et al., 2003). Markus et al. also reported a positive association of D allele with lacunar infarction (Markus et al., 1995).
Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes.
Angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population
2008, Journal of the Neurological Sciences
Stroke is one of the most complex diseases with several subtypes, arising from numerous gene–gene and gene–environmental interactions. The aim of our study was to investigate whether the insertion/deletion polymorphism in Angiotensin-converting enzyme gene is associated with ischemic stroke in a South Indian population. One hundred and sixty two patients and one hundred and fifty controls were studied for the presence of ACE gene polymorphism by PCR technique. The stroke patients were subtyped according to TOAST criteria, taking into account all the available data. There were significant differences in the genotypic distribution and allelic frequency between the patients and healthy controls. Furthermore the D allele was significantly associated with intracranial large artery atherosclerosis. However, the association was insignificant with other stroke subtypes. We observed that ACE ID/DD genotypes are associated with an elevated incidence of stroke in a South Indian population from Andhra Pradesh. Moreover, ACE gene polymorphism was found to contribute to the risk of developing intracranial large artery atherosclerosis, which is the most frequent subtype in this region.
Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke
2006, Journal of Clinical Neuroscience
Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with increased incidence of stroke in some populations, although contradictory results have been reported. The aim of this study was to determine the allelic frequency and the genotypic distribution for ACE gene polymorphism in Turkish patients with ischemic stroke compared to appropriate healthy controls and to correlate the genetic findings with stoke type. One hundred and eight patients with ischemic stroke versus 79 healthy controls were studied for the presence of ACE gene polymorphism detected by PCR. Genotypes were defined as DD, II and ID according to the presence of the D (deletion) and I (insertion) alleles. There was no statistically significant difference in either the genotypic distribution or allelic frequency between the patients versus healthy controls (χ² = 0.105; df = 1; p = 0.430). There was also no significant difference for ACE genotype distribution and allelic frequency within the stroke group classified according to Bamford criteria (χ² = 4.827; df = 3; p = 0.185). Our data supports lack of association between DD genotype and/or D allele and ischemic stroke or subtypes of ischaemic stroke in the Turkish population.
Role of ACE Polymorphism in Acute Ischemic Stroke
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Candidate-gene analysis of white matter hyperintensities on neuroimaging
2016, Journal of Neurology, Neurosurgery and Psychiatry

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Renin-angiotensin system gene polymorphism in Japanese stroke patients

Abstract

Introduction

Section snippets

Subjects

Method

Patients profile

Discussion

Acknowledgments

Am. J. Hypertens.

Biochem. Biophys. Res. Commun.

Am. J. Hypertens.

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

J. Clin. Invest.

Ischemic stroke and the gene for angiotensin-converting enzyme in Japanese hypertensives

Circulation