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(Circulation. 1996;93:1630-1633.)
© 1996 American Heart Association, Inc.

Articles

Ischemic Stroke and the Gene for Angiotensin-Converting Enzyme in Japanese Hypertensives

Kazuomi Kario, MD, PhD; Nobuyuki Kanai, MD, PhD; Ken Saito, MD, PhD; Naoki Nago, MD, PhD; Takefumi Matsuo, MD, PhD; Kazuyuki Shimada, MD, PhD

From the Department of Internal Medicine, Awaji-Hokudan Public Clinic (K.K.), Hyogo, Japan; Hyogo (Japan) Prefectural Awaji Hospital (K.K., T.M.); and the Department of Pathology (N.K., K. Saito), Department of Community and Family Medicine (N.N.), and Department of Cardiology (K. Shimada), Jichi Medical School, Tochigi, Japan.

Correspondence to Dr Kazuomi Kario, 480, Ikuha, Hokudan, Tsuna, Hyogo, 656-16, Japan.

	Abstract

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Background The ACE insertion/deletion (I/D) polymorphism is reported to be associated with myocardial infarction in both whites and Japanese. However, there have been no reports on the association of this polymorphism with stroke in each race. Furthermore, there are some racial differences in the demographics of cardiovascular diseases. In Japanese, stroke (especially that which occurs in preexisting hypertension) is more common and coronary artery disease much less common than in whites. We propose that the ACE I/D polymorphism might be associated with hypertensive cerebrovascular disease in Japanese.

Methods and Results To study the association between the ACE I/D polymorphism and hypertensive cerebrovascular disease, we identified the ACE I/D genotype in 228 hypertensive and 104 normotensive Japanese subjects. Compared with its frequency (0.31) in the 90 hypertensives without lacunae detected by magnetic resonance imaging, the ACE*D allele frequency was significantly higher (0.47; P<.001) in the 138 hypertensives with silent or clinically overt ischemic stroke, whereas there was no significant difference between its frequency in hypertensives without lacunae and in 104 normotensive control subjects (0.34). The positive association between the ACE I/D genotype and ischemic stroke in hypertensive patients was independent of other risk factors.

Conclusions We found a positive association between the ACE*D allele and ischemic stroke in Japanese hypertensives in our study. The ACE*D allele may be an independent risk factor for the development of cerebrovascular disease in hypertensive patients.

Key Words: cerebrovascular disorders • enzymes • genes • hypertension

	Introduction

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Ischemic stroke represents a leading cause of death in most developed countries, together with coronary artery disease. In contrast with coronary artery disease, only a few important risk factors have been established for stroke: age, smoking, and high blood pressure. Dyslipidemias that are important in the assessment of coronary risk are far less reliable for identification of individuals at risk of stroke. Hypertension is a well-known and important risk factor for stroke, but not all hypertensive patients develop stroke. Some additional determinants might also operate in the development of stroke.

Genes that influence the renin-angiotensin system are potentially etiologic candidates for causing cardiovascular disease because their products exert a profound systemic effect on vasoconstriction and ACE inhibitors reduce the risk of cardiovascular disease. This supposition is supported by recent reports that the ACE I/D polymorphism is associated with increased risk for myocardial infarction in whites^{1 2} and Japanese.³ However, there have been no reports on the association of this polymorphism and stroke. There are some racial differences in the demographics of cardiovascular diseases. In Japan, stroke (especially that which occurs in preexisting hypertension) is more common and coronary artery disease much less common than in western countries.⁴ We propose that the ACE I/D polymorphism might be associated with hypertensive cerebrovascular disease in Japanese.

	Methods

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Subjects
We studied 228 hypertensive patients (83 patients with clinically overt ischemic stroke [clinically overt stroke group] and 145 asymptomatic patients) and 104 normotensive control subjects. For assessment of silent hypertensive cerebrovascular disease, MRI was performed in all 145 asymptomatic hypertensive patients and was used to classify them into a nonstroke group without lacunae (n=90) and a silent stroke group with one or more lacunae (n=55). We combined the hypertensive silent stroke group and the clinically overt stroke group into the stroke group. The age- and sex-matched control group consisted of 104 healthy normotensive subjects (40 years of age) who attended an annual health examination. The subjects all resided in the same district (Awaji-Hokudan), and they did not include any first-degree relatives.

Ischemic stroke was diagnosed when neurological deficits were accompanied by corresponding abnormal findings depicted by brain CT, MRI, and/or magnetic resonance angiography and was classified on the basis of the clinical categories established by the National Institute of Neurological Disorders and Stroke,⁵ as described practically by Takano et al.⁶

Brain MRI
Brain MRI was performed with a superconducting magnet with a main field strength of 1.5 T (Toshiba MRT 200 FXII). The brain was imaged in the axial plane in 8-mm-thick slices. T1-weighted images were obtained by use of a short spin-echo pulse sequence with a repetition time of 500 ms and an echo time of 13 ms. T2-weighted images were obtained by use of a long spin-echo pulse sequence with a repetition time of 4000 ms and echo times of 60 and 112 ms. The matrix was 256x224 pixels. The images were evaluated for the number and location of lacunae. Lacunae were strictly defined as low–signal intensity areas (<1 cm) on T1-weighted images, which were visible as hyperintense lesions on T2-weighted images as illustrated previously.⁷ Lacunae as defined above might include lesions other than true infarcts such as état criblé, especially if their size were small (ie, <5 mm).⁷ All of the MRI images were interpreted in a blind fashion.

Detection of ACE I/D Polymorphism
We extracted genomic DNA from citrated whole blood using salt/chloroform by a modification of a previously described method.⁸ Enzymatic amplification of DNA was performed by PCR with 0.1 µg of DNA extract and thermostable Taq polymerase (Takara Biochemical) according to the manufacturer's instructions.^{9 10} The PCR was performed in a thermal reactor (MJ Research). The oligonucleotide sequences of the PCR primers were 5'-CTGCAGACCACTCCCATCCTTTCT-3' and 5'-GATGTGGCCATCACATTCGTCAGAT-3'.¹¹ The DNA was amplified for 35 cycles with denaturation at 94°C for 30 seconds, annealing at 60°C for 30 seconds, and extension at 70°C for 60 seconds. The PCR products were separated by electrophoresis on 3% agarose gel (NuSieve 3:1 agarose gel, FMC Bioproducts) in 45 mmol/L tris-borate and 1 mmol/L EDTA (pH 7.7) containing 0.5 mg/mL ethidium bromide and were visualized by use of UV light.

Identification of the ACE genotype of all samples was made in a blind manner by the same investigator (N.K., who is a professional in identification of the ACE genotype).

Statistical Analysis
Statistical analysis was performed with the Statistical Analysis System (version 6.03; SAS Institute, Inc). Allele frequencies in different groups were compared by use of gene counting and ² analysis. After one-way ANOVA, Scheffé's F test was used for comparison between the mean values for the two groups. In the multivariate logistic regression analysis in 228 hypertensive patients, ischemic stroke (silent or clinically overt stroke) was the dependent variable and the independent variables were age (by 10-year groups), sex (1=male, 2=female), smoking status (1=nonsmoker, 2=current or ex-smoker), ECG-LVH (1=absent, 2=present), family history of known stroke or sudden death (1=absent, 2=present), metabolic variables (hematocrit, total cholesterol level, HDL-cholesterol level, and glucose level, based on a 1 SD difference of each variable in the total group of hypertensive patients), and ACE genotype (1=II; 2=ID+DD). The association between differences with a probability value less than .05 was considered significant.

	Results

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The ACE I/D polymorphism detected by PCR was evident as a 490-bp product in the presence of the insertion (I allele) and as a 190-bp fragment in the absence of the insertion (D allele). Thus, each DNA sample presented one of three possible patterns after electrophoresis: a 190-bp band (genotype DD), both a 190- and a 490-bp band (genotype ID), or a 490-bp band (genotype II), as shown in the Figure.

View larger version (41K): [in this window] [in a new window]   Figure 1. PCR products from amplification of the polymorphic region in intron 16 of the ACE gene. Lane DD contains the 190-bp product from a DD homozygote; lane ID, the products from an ID heterozygote with both the 490- and 190-bp fragments; lane II, the 490-bp product from an II homozygote; and lane M, markers.

The clinical and metabolic characteristics of the subjects studied are shown in Table 1. There were no significant differences among the three groups in prevalence of current or ex-smokers, those with family history of known stroke or sudden death, or any metabolic variable. In 228 hypertensive patients, male sex and ECG-LVH were more common in the stroke group than in the nonstroke group (P<.05).

View this table: [in this window] [in a new window]   Table 1. Clinical and Metabolic Characteristics of Hypertensive Patients With and Without Ischemic Stroke and Normotensive Control Group

The ACE genotype distributions of the hypertensive stroke group were significantly different not only from those in the normotensive control group but also from those in the hypertensive nonstroke group (Table 2), whereas there was no significant difference between those in the hypertensive nonstroke group and the normotensive control group. Compared with its frequency (0.31) in the nonstroke group, the ACE*D allele frequency was significantly higher in the stroke group (0.47; P<.001), whereas there was no significant difference between frequency of this allele in the nonstroke group and the normotensive control group (0.34). There was no significant difference in frequency of the ACE*D allele between the clinically overt stroke group (0.50) and the silent stroke group (0.44), and both were significantly higher than in the nonstroke group (P<.05).

View this table: [in this window] [in a new window]   Table 2. ACE I/D Genotype Distributions and Gene Frequencies in Hypertensive Patients With and Without Ischemic Stroke and in Normotensive Control Group

In all 332 subjects studied (the 104 normotensive control subjects and 228 hypertensives), a significant increase in the prevalence of clinically overt ischemic stroke was found across the three ACE genotypes, with higher values associated with the ACE*D allele (41% in those with the DD genotype, 27% in those with the ID genotype, and 16% in those with the II genotype; ²=12.1, P<.005). The ACE genotype distribution of the subjects with a family history of known stroke or sudden death (II=21 [30%], ID=31 [45%], DD=17 [25%]) was also significantly different from that of those without such family history (103 [39%], 127 [48%], and 33 [13%], respectively; ²=6.55, P<.05). Frequency of the ACE*D allele was also significantly higher in the former group than in the latter (0.46 versus 0.37; ²=4.99, P<.05). In the association study between the ACE genotype and risk factors listed in Table 1, no risk factor except family history was associated with the ACE genotype.

In the multivariate logistic regression analysis of hypertensive patients (Table 3), ischemic stroke (silent or clinically overt) was independently associated with ACE genotype (OR=2.44, P<.005) and age (OR=1.61, P<.01).

View this table: [in this window] [in a new window]   Table 3. Multiple Logistic Regression Analysis With Ischemic Stroke as the Dependent Variable in Hypertensive Patients

	Discussion

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To the best of our knowledge, the present study is the first clarification of a close association of the ACE I/D polymorphism and hypertensive cerebrovascular disease. Our results indicate the important role of the renin-angiotensin system in the pathogenesis of both silent and clinically overt ischemic strokes in hypertensive patients, although the precise mechanism remains unknown.

Frequency of the ACE*D allele was significantly higher in the hypertensive stroke group than in the hypertensive nonstroke group or in the group of normotensive control subjects. The ACE I/D polymorphism is responsible in part for the interindividual variation in plasma ACE levels, such that subjects with the DD genotype have approximately twice the plasma levels of ACE compared with those with the II genotype.¹² The ACE I/D polymorphism identifies genetic variants that may contribute to the risk of ischemic stroke through increased vasoconstriction, cellular hypertrophy, and thrombosis after an increase in angiotensinogen II levels and the inactivation of bradykinin.¹³ These possibilities are supported by the clinical and experimental observations that after the administration of an ACE inhibitor, cerebral blood flow is well maintained and a downward shift in the limits of autoregulation may occur.¹⁴ Increased levels of immunoreactive angiotensin II, angiotensin II binding sites, and ACE in the cerebrospinal fluid have been reported in the spontaneously hypertensive rat.¹⁵ Thus, the role of the renin-angiotensin system in the brain might be greater in hypertensives than in normotensives.

Overall, a significant increase in the prevalence of clinically overt ischemic stroke and family history of known stroke or sudden death was found across the three ACE genotypes, with higher values associated with the ACE*D allele. These results also support the concept of a close association of the ACE I/D polymorphism with hypertensive cerebrovascular disease.

Previously, the ACE gene polymorphism was reported to be unrelated to essential hypertension in whites,^{1 2 16 17 18} although at least one report did not support this.¹⁹ This discrepancy also was found in studies of Japanese.^{20 21} However, no thorough evaluation of hypertensive target organ damage has been performed. Indeed, in the present study as well, the distribution of ACE genotypes and the frequency (0.36) of the D allele in the entire group of asymptomatic hypertensives combined with nonstroke and silent stroke groups were no different from those in the normotensive control group. We evaluated silent cerebrovascular disease by MRI, which is the most sensitive method for detection of hypertensive cerebrovascular damage,⁷ and we found that frequency of the ACE*D allele was significantly higher in the silent stroke group than in the nonstroke group (0.44 versus 0.31; ²=5.10, P<.05). The absence of any difference in frequency of the ACE*D allele between the silent stroke group and the clinically overt stroke group indicates the important contribution of the renin-angiotensin system to the pathogenesis of lacunae formation, even in the clinically silent stage.

Frequencies of the ACE*D allele in the asymptomatic hypertensive (0.36) and normotensive control groups (0.34) were lower than those reported previously for westerners and for Japanese populations (0.4 to 0.6).^{1 2 3 11 17 18 19 20} Since our normotensive control group consisted of healthy participants in annual health examinations, the lower frequency of the ACE*D allele is probably characteristic of our district.

In conclusion, we found a positive association between the ACE*D allele and ischemic stroke in our study of Japanese hypertensives. This association was independent of other risk factors, including ECG-LVH. Thus, the ACE*D allele may be an independent risk factor for the development of cerebrovascular disease in hypertensive patients. The consistency of our results in different racial populations and their pathological relevance still need to be assessed by larger prospective association studies or linkage-based family studies.

	Selected Abbreviations and Acronyms

 

ECG-LVH = left ventricular hypertrophy as detected by ECG I/D = insertion/deletion MRI = magnetic resonance imaging OR = odds ratio PCR = polymerase chain reaction

	Acknowledgments

 
This study was supported by grants-in-aid from the Foundation for the Development of the Community, Tochigi, Japan.

Received December 4, 1995; revision received February 14, 1996; accepted February 16, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kario, K. Articles by Shimada, K. Search for Related Content PubMed PubMed Citation Articles by Kario, K. Articles by Shimada, K.