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(Hypertension. 1995;25:950-953.)
© 1995 American Heart Association, Inc.

Articles

Enhanced Predictability of Myocardial Infarction in Japanese by Combined Genotype Analysis

Atsushi Kamitani; Hiromi Rakugi; Jitsuo Higaki; Mitsuru Ohishi; Shang-Jin Shi; Seiju Takami; Yukiko Nakata; Yorihiko Higashino; Kenshi Fujii; Hiroshi Mikami; Tetsuro Miki; Toshio Ogihara

From the Department of Geriatric Medicine, Osaka (Japan) University Medical School (A.K., H.R., J.H., M.O., S.-J.S., S.T., Y.N., H.M., T.M., T.O.); and the Division of Cardiology, Sakurabashi-Watanabe Hospital, Osaka (Y.H., K.F.), Japan.

Correspondence to Toshio Ogihara, MD, Department of Geriatric Medicine, 2-2 Yamada-oka, Suita, Osaka 565, Japan.

	Abstract

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Abstract To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n=103) and control subjects (n=103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P<.05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P<.0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.

Key Words: myocardial infarction • angiotensinogen • angiotensin-converting enzyme • genotype

	Introduction

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Coronary heart disease (CHD) remains a major public health problem in industrialized countries because of its major contribution to total mortality. Large international differences in the trends in CHD incidence and mortality have been reported.¹ A number of risk factors for coronary arteriosclerosis, including hyperlipidemia, obesity, hypertension, cigarette smoking, male sex, and diabetes mellitus, have been well documented epidemiologically based on their relationship to the incidence of CHD.² The angiotensin-generating system has long been known to contribute to the development of CHD, and recently, several multicenter clinical trials have revealed that angiotensin-converting enzyme (ACE) inhibitors are effective in reducing the recurrence of myocardial infarction (MI)³ and preventing neointimal formation after vascular injury with a balloon catheter in rats.

Polymorphism of both angiotensinogen (a change of nucleotide in exon 2 resulted in an amino acid change from methionine [M] to threonine [T]) and the ACE gene (insertion/deletion [I/D] polymorphism located in intron 16) is associated with an augmentation of angiotensin generation,^{4 5} which may contribute to the development of CHD. Previous studies showed that the ACE-DD genotype was significantly more frequent in patients with MI than in control subjects.^{6 7} Furthermore, we have reported that the ACE-DD genotype may be a potent genetic risk factor for restenosis after percutaneous transluminal angioplasty (PTCA).⁸ It has been reported that a molecular variant of the angiotensinogen gene, with threonine instead of methionine at position 235 (M235T), may represent a preserved inherited predisposition for essential hypertension in Caucasians⁵ and Japanese.⁹ It is possible that polymorphisms of the genes related to the angiotensin-generating system may contribute to cardiovascular disease, such as MI and essential hypertension.

In this study, we performed association studies of the polymorphisms of the angiotensinogen and ACE genes to explore the genes responsible for MI and restenosis after PTCA. Furthermore, to detect a genetically high risk group for MI, we attempted combined classification according to the genotypes of these genes.

	Methods

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Patient Selection
MI Patients and Control Subjects
A total of 206 unrelated male Japanese individuals were random patients at Osaka University Hospital, Sakurabashi-Watanabe Hospital, and Sakuragaoka Hospital. Informed consent was obtained from the patients or their relatives before blood samples were drawn for DNA analysis. One hundred three of the patients, aged 65 years or younger, had suffered at least one MI from January 1990 through March 1993. Patients were randomly recruited on the day of their admission to the hospital. All patients were diagnosed as having MI by coronary angiography, electrocardiographic criteria, and measurements of heart-specific serum enzymes. One hundred three control subjects without cardiovascular disease—but matching the MI group for age, sex, body mass index (BMI), blood pressure, total cholesterol level, and history of diabetes mellitus and smoking—were randomly selected from among 477 subjects attending the same hospitals for voluntary health screening (75 subjects) or because of transient noncardiovascular symptoms (28 subjects). None of the 103 control subjects had a history of CHD, and all had normal electrocardiograms during both rest and physical stress. Individuals with essential hypertension were excluded because the TT genotype of the angiotensinogen gene has been found to be a hypertensive gene in Japanese.⁹ The mean±SEM age of the patients was 52±1 years and that of the control subjects was 54±1 years.

MI Patients With Successful Emergency PTCA
Ninety-one consecutive cases of acute MI with successful direct angioplasty (defined as achieving a visually assessed stenosis of <50% of the vessel diameter after angioplasty) within 24 hours of the onset of MI were studied. Follow-up coronary angiography (CAG) was performed between 3 and 6 months after PTCA. In some cases, CAG was performed at the clinically estimated time of restenosis, such as the onset of recurrent angina. In the follow-up CAG, restenosis was arbitrarily defined as a greater than 50% reduction in the luminal diameter of the stenosis compared with the diameter of the CAG taken immediately after the angioplasty. Other subjects were defined as the non-restenosis group.

Detection of Genetic Polymorphism
Angiotensinogen Gene
DNA was extracted from peripheral blood leukocytes as described previously.¹⁰ Polymerase chain reaction (PCR) was performed according to the method of Russ et al¹¹ with some modification. In brief, the sequences of the downstream and upstream primers were 5'-CAG GGT GCT GTC CAC ACT GGA CCC C-3' (mismatches shown by underline) and 5'-CCG TTT GTG CAG GGC CTG GCT CTC T-3', respectively. Two mismatches in the downstream primer were introduced to produce the corresponding half-site for Tth111-I. These locate at positions 4 and 5 from its 3' end and do not interfere with elongation. PCR was performed in a final volume of 10 µL containing 100 ng of genomic DNA, 20 pmol of each primer, each of the four dNTPs at 250 µmol/L, 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 10 mmol/L Tris-HCl at pH 8.4, and 1 U Taq polymerase (Perkin-Elmer Cetus). Amplification was carried out in a DNA Thermal Cycler PJ 2000 (Perkin-Elmer Cetus). Cycling conditions after an initial denaturation step (at 90°C for 1 minute) were as follows: 10 cycles with steps of denaturation at 94°C for 1 minute, annealing at 68°C for 1 minute, and extensions at 72°C for 1 minute and 72°C for 1 minute, followed by 30 cycles with steps of denaturation at 90°C for 30 seconds, annealing at 68°C for 1 minute, extension at 72°C for 30 seconds, and final extension at 72°C for 10 minutes. The 3 µL of unpurified product was diluted to 10 µL in the recommended restriction buffer containing 5 U Tth111-I (Takara Shuzo Co, Ltd) and digested for at least 2 hours at 65°C. Samples were applied to 10% polyacrylamide gel and subjected to electrophoresis at 200 V for 45 minutes. The DNA was visualized directly by ethidium bromide staining.

ACE Gene
PCR was performed according to the method of Tiret et al.¹² The sequences of the sense and antisense primers were 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3' and 5'-GAT GTG GCC ATC ACA TTC GTC AGA T-3', respectively. PCR was performed in a final volume of 50 µL that contained 100 ng of genomic DNA, 20 pmol of each primer, 250 µmol/L of each of the four dNTPs, 3.0 mmol/L MgCl₂, 50 mmol/L KCl, 10 mmol/L Tris-HCl at pH 8.4, and 0.4 U Taq polymerase. Amplification was carried out in the DNA Thermal Cycler PJ 2000 for 30 cycles with steps of denaturation at 94°C for 1 minute, annealing at 58°C for 1 minute, and extension at 72°C for 1 minute. The PCR products were subjected to electrophoresis in 2% agarose gel, and then DNA was visualized directly by ethidium bromide staining.

Statistical Analysis
Values of the clinical characteristics of the two groups are expressed as mean±SEM and were compared using the unpaired Student's t test. Allele frequencies were deduced from genotype frequencies, and the difference between groups was tested by ² analysis with 1 df. No evidence of significant deviations from Hardy-Weinberg equilibrium was found in these Japanese population samples. The odds ratio (OR) and the 95% confidence interval (CI) were calculated.

	Results

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Genetic Risk for MI
Table 1 shows the characteristics of the study population. Several variables considered to be risk factors for MI, such as age, BMI, systolic and diastolic blood pressures, total cholesterol level, and history of diabetes mellitus and smoking, were compared between the genotypes of the angiotensinogen gene in both the MI and control groups. Although BMI was matched between the MI group and the control group, BMI of the non-TT genotype was lower in the control group compared with the MI group.

View this table: [in this window] [in a new window]   Table 1. Comparison of Variables Between Angiotensinogen Genotypes in Myocardial Infarction Patients and Control Subjects

PCR amplified a 165-bp segment including the M235T polymorphism of the angiotensinogen gene. The restriction enzyme Tth111-I cleaved the 165-bp PCR product into 141- and 24-bp fragments for the allele that contained the Tth111-I restriction site in the presence of threonine transition. This allele was designated as T. The allele that lacked the Tth111-I restriction site was designated as M. Thus, each DNA sample yielded one of three possible genotypes, either MM, MT, or TT. Table 2 summarizes the frequencies of angiotensinogen genotypes in MI patients and control subjects. The TT genotype was significantly more frequent in the MI group than in the control group compared with the two other genotypes (MM and MT) (P<.05). Frequencies of the MM, MT, and TT genotypes, respectively, were 0.06, 0.30, and 0.64 in the MI patients and 0.10, 0.40, and 0.50 in the control subjects. The OR (estimate of the relative risk of MI in subjects with the TT genotype compared with subjects with the MM or MT genotypes) was 1.75, with a 95% CI of 1.00 to 3.06. The ACE-DD genotype was significantly more frequent in the MI group than in the control group compared with the two other genotypes in Japanese, which confirms the results of our previous study.⁸ Frequencies of the II, ID, and DD genotypes, respectively, were 0.30, 0.33, and 0.37 in the MI patients and 0.44, 0.44, and 0.12 in the control subjects (P<.0001, OR=4.43, 95% CI=2.16 to 9.12). To evaluate the genetically high risk groups for MI, we attempted combined classification according to the genotypes of the two genes (Table 2). The OR estimated by combined analysis with the angiotensinogen-TT and ACE-DD genotypes was markedly increased compared with that estimated separately from the angiotensinogen-TT or ACE-DD genotype. The wide CI for the calculated OR of the combined analysis is due to the presence of a one-digit number in the column. However, the lower limit of 95% CI in the combined analysis was still higher than those estimated separately from each genotype (Table 2).

View this table: [in this window] [in a new window]   Table 2. Frequencies of Angiotensinogen Genotypes in Myocardial Infarction Patients and Control Subjects and Combined Analysis of the Angiotensinogen and ACE Genes

Genetic Risk for Restenosis After PTCA
Age, BMI, systolic and diastolic blood pressures, total cholesterol level, duration from PTCA to follow-up CAG, smoking habit, frequency of hyperlipidemia, and frequency of diabetes mellitus did not differ between the restenosis (n=38) and non-restenosis (n=53) groups. The frequencies of the MM, MT, and TT genotypes, respectively, were 0.08, 0.34, and 0.58 in the restenosis group and 0.04, 0.36, and 0.60 in the non-restenosis group (P=NS) The frequencies of ACE genotypes in the restenosis and non-restenosis groups were confirmed in our previous study.⁹ The frequencies of the II, ID, and DD genotypes, respectively, were 0.13, 0.23, and 0.64 in the restenosis group and 0.36, 0.36, and 0.28 in the non-restenosis group (P<.005, OR=4.23, 95% CI=1.72 to 10.38). The combined classification with the angiotensinogen-TT and ACE-DD genotypes did not show any further usefulness of evaluation of the genetically high risk group for restenosis after PTCA in contrast to the usefulness of the combined analysis for MI. The frequencies of the angiotensinogen-TT and ACE-DD genotypes together and the other genotypes were 0.29 and 0.71, respectively, in the restenosis group and 0.21 and 0.79, respectively, in the non-restenosis group (P=NS).

	Discussion

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The present study demonstrated that the angiotensinogen-TT genotype is more frequent in MI patients than in control subjects in a Japanese population. Although this association was marginal, the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of MI compared with separate association analysis of each gene.

The precise mechanism by which these gene polymorphisms interact with the risk of MI is unclear. It has been reported that the angiotensinogen-TT genotype and the ACE-DD genotype are associated with higher levels of circulating angiotensinogen⁵ and ACE,⁴ respectively. Both angiotensinogen and ACE are important factors in angiotensin generation. The previous study reported that long-term exposure to high levels of plasma ACE activity resulted in vascular wall thickening.¹³ Recent investigations¹³ revealed that angiotensin II (Ang II) causes not only vasoconstriction but also both hypertrophic growth of smooth muscle cells and cardiac cells and hyperplasia of smooth muscle cells via autocrine and paracrine mechanisms. Furthermore, a contribution of Ang II to cardiac events was suggested by the reports that long-term treatment with ACE inhibitors reduced the incidence of recurrent MI¹⁴ and that a high renin-sodium profile is associated with a higher risk of MI in hypertensive individuals.¹⁵ Tiret et al¹⁶ reported that the ACE and Ang II receptor subtype 1 genes interact with the risk of MI in Caucasians. They also speculated that the gene variants of the ACE and Ang II receptors could interact to generate Ang II through a local paracrine mechanism.

Another interpretation is that either the angiotensinogen gene or ACE gene may confer susceptibility to cardiovascular disease via a system unrelated to angiotensin generation. As there are several reports^{6 7} on the significant association between MI and the ACE-DD genotype, the gene responsible for MI should be closely located to the I/D polymorphic locus of ACE. However, there is no direct evidence that M235T polymorphism of the angiotensinogen gene or I/D polymorphism of the ACE gene is related to the regulation of vascular angiotensin generation. It is not even known whether these polymorphisms are causative variants or just markers of another functional variant. Further studies are necessary to determine the responsible genetic locus for each cardiovascular disease and whether the angiotensinogen and ACE genes themselves, and not other genes, confer susceptibility to cardiovascular events.

MI has a multifactorial etiology resulting from the interaction of genetic and environmental components. It is well documented that the incidence of MI increases additively with an increase in the number of coronary risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. The genetic pathogenesis of MI may involve multiple genes. Therefore, our demonstration of an increase in the predictability of MI by combined genetic analysis with angiotensinogen and ACE is in accord with the presumption that the accumulation of genetic risk factors increases the incidence of MI as well as the accumulation of environmental risk factors. It is not clear from the results of the present study whether the gene polymorphisms of angiotensinogen and ACE independently predict genetic susceptibility to MI because the study population was not large enough to allow definite conclusions. The independence of genetic susceptibility to MI between angiotensinogen and ACE is unclear because the study population was not large enough to analyze it. However, the angiotensinogen and ACE genes are mapped to chromosomes 1 and 17, respectively, and there was no segregation distortion between the two genes.

Furthermore, we performed combined analysis for restenosis after successful direct PTCA to estimate whether the interaction between angiotensinogen and ACE gene polymorphisms on the risk of various cardiovascular diseases is a universal one. Restenosis after direct PTCA is one such cardiovascular event in which the ACE-DD genotype is a known genetic risk factor.⁸ However, the angiotensinogen-TT genotype in the present study showed no association with the incidence of restenosis in contrast to the ACE-DD genotype, and the combined analysis of the two genes did not enhance the predictability of restenosis.

It is noteworthy that the frequency of the angiotensinogen-TT genotype (0.50) in the control group was higher than the previously reported value of 0.36 in Caucasians. Since it has been noted that the ACE gene is associated with essential hypertension in Australians¹⁷ but not in Japanese,¹⁸ further studies are necessary to determine whether the angiotensinogen-TT genotype or combined analysis with the ACE-DD genotype is a potent new risk factor for MI in different ethnic groups.

The present study demonstrated the usefulness of the angiotensinogen-TT genotype in predicting MI but not restenosis after PTCA in combined analysis with the ACE-DD genotypes. However, it has been reported that the CA repeat of the angiotensinogen gene, which exists in the 3' flanking region, is associated with essential hypertension in populations from the United Kingdom.¹⁹ In the present study, we did not perform an association study of this CA repeat of the angiotensinogen gene with MI in Japanese. It is possible that some molecular variants of the angiotensinogen gene besides M235T may also be a marker for MI in Japanese. More work is required in the Japanese population to definitely prove this possibility.

In conclusion, the present study showed that the TT genotype of the angiotensinogen gene may be a predictor for MI and provided evidence that combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of MI in Japanese. Its clinical usefulness remains to be confirmed.

Received September 27, 1994; first decision November 16, 1994; accepted January 11, 1995.

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