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(Circulation. 1995;91:951-954.)
© 1995 American Heart Association, Inc.

Articles

Molecular Variant of Angiotensinogen Gene Is Associated With Coronary Atherosclerosis

Tomoaki Ishigami, MD; Satoshi Umemura, MD; Tamio Iwamoto, MD; Kouichi Tamura, MD; Kiyoshi Hibi, MD; Satoshi Yamaguchi, MD; Nobuo Nyuui, MD; Kazuo Kimura, MD; Naomichi Miyazaki, MD; Masao Ishii, MD

From the Second Department of Internal Medicine, Yokohama City University School of Medicine (Japan).

Correspondence to Satoshi Umemura, MD, Second Department of Internal Medicine, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama 236, Japan.

	Abstract

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Background A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensinogen gene and coronary atherosclerosis.

Methods and Results This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with >25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated AA, Aa, and aa. The a allele indicated thymine-cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the AA, Aa, and aa allelles, respectively. There was an excess in the a allele among patients (P<.01).

Conclusions We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensinogen gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis.

Key Words: coronary atherosclerosis • polymerase chain reaction • genes

	Introduction

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Coronary atherosclerosis is a common disease that causes ischemic heart diseases, such as angina pectoris and myocardial infarction. Coronary risk factors, such as hypertension, hypercholesterolemia, and diabetes mellitus, are known to cause this disorder. In addition, recently, the gene polymorphisms of angiotensin-converting enzyme (ACE)¹ and apolipoprotein E² have been reported as independent risk factors for myocardial infarction, although the genetic cause of this disorder has not been proved completely.

Angiotensinogen is the substrate of renin and the precursor to angiotensin peptide, a powerful vasoconstrictive agent in humans. Various molecular variants of the angiotensinogen gene have been reported. One molecular variant of angiotensinogen that exists in exon 2, consisting of the thymine-cytosine transition at nucleotide 704, has been reported to be associated with hypertension in Caucasians³ and in Japanese.^{4 5} However, another study of Caucasians in the United Kingdom failed to show any correlation between this variant and hypertension.⁶ This variant of the angiotensinogen gene may also be associated with preeclampsia.⁷

In this study, we analyzed the point mutation of the angiotensinogen gene by use of polymerase chain reaction (PCR) and compared the frequencies of these alleles in patients with coronary atherosclerosis and control subjects. We found a significant difference between them; this mutation was more frequent in the patients, suggesting a new risk factor for coronary heart disease.

	Methods

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The subjects in this study were all Japanese, all aged >30 years old, and consisted of 82 patients with coronary atherosclerosis and 160 control subjects. The patients each had at least one coronary artery with >25% luminal diameter obstruction on average according to multiple coronary angiographic views. The control subjects had been admitted to our hospital with other diseases and had no symptoms or no signs of coronary artery diseases. Several characteristics of these two groups were not significantly different (Table 1).

View this table: [in this window] [in a new window]   Table 1. Comparison of Characteristics in Patients With Coronary Atherosclerosis Versus Control Subjects

Blood samples of 10 mL were drawn into heparinized tubes, and white blood cells were separated. The genomic DNA was extracted from the peripheral blood leukocytes by the standard method by use of proteinase K digestion of nuclei.⁸ Phenol extraction was followed by ethanol precipitation of the DNA.

PCR was performed according to the method of Russ et al,⁹ with some modification. The sequences of the downstream and upstream primers were as follows: upstream primer, 5'-CGT TTG TGC AGG GCC TGG CTC TC-3'; downstream primer, 5'-AGG GTG CTG TCC ACA CTG GAC CC-3'. The thymine-cytosine transition at nucleotide 704 in exon 2 does not alter a restriction site but does produce a "half-site" for Tth111I (GACNNNGTC). Introduction of the corresponding half-site is achieved by a PCR primer with two mismatches underlined. These are located at positions 3 and 4 from its 3' end and do not interfere with elongation. Amplification yields a product of 163 bp. In the presence of cytosine at position 704, cleavage by Tth111I generates a 140-bp fragment.

The PCR was performed in a final volume of 20 µL that contained 200 ng genomic DNA, 20 picomoles of each primer, each of four dNTP at 250 mmol/L, 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 10 mmol/L Tris HCl at pH 8.4, and 2 U Taq polymerase (TAKARA). The cycling condition was as follows: an initial denaturation step at 90°C for 3 minutes; 10 cycles at 94°C for 1 minute, 68°C for 1 minute, and 72°C for 1 minute; 30 cycles at 90°C for 30 seconds, 68°C for 30 seconds, and 72°C for 30 seconds; and final extension at 72°C for 10 minutes. Then 2 µL unpurified product was diluted to 10 µL in the recommended restriction buffer containing 12 U Tth111I (TAKARA) and digested for at least 2 hours at 65°C. These samples were applied to 8% polyacrylamide gel and subjected to electrophoresis at 100 mA for 1 hour. The DNA was visualized directly by ethidium bromide staining.

For comparison of alleles and genotype frequency, we analyzed the data by ² test. The clinical characteristics of the two groups were expressed as mean±SEM and were compared by unpaired Student's t test.

	Results

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The Figure shows a representative polyacrylamide gel in which the PCR products were amplified from human genomic DNA and digested by restriction enzyme Tth111I. The allele that lacked the enzyme-restriction site was designated A (163 bp). On the other hand, the allele that had the enzyme-restriction site in the presence of cytosine transition at nucleotide position 704 was designated a (140 bp). Thus, there were three possible genotypes, ie, AA, Aa, and aa.

View larger version (114K): [in this window] [in a new window]   Figure 1. Polyacrylamide gel electrophoresis image showing polymerase chain reaction products amplified from human genomic DNA and digested by restriction enzyme Tth111I.

Table 1 shows the profiles of the study participants in the two groups. These patients and subjects were all aged >30 years. There were no significant differences between subject characteristics in these two groups.

Table 2 shows the results of the angiotensinogen genotype analysis. The frequencies of AA, Aa, and aa genotypes were 7.3%, 26.8%, and 65.9%, respectively, in the patients and 18.8%, 31.9%, and 49.3% in the control subjects, respectively. There was an excess in the a allele in patients with coronary atherosclerosis compared with control subjects (P<.01).

View this table: [in this window] [in a new window]   Table 2. Genotype Distribution and Allelle Frequencies of the Angiotensinogen Gene in Patients With Coronary Atherosclerosis Versus Control Subjects

	Discussion

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In this study, we have shown that one of the molecular variants of the human angiotensinogen gene may be involved in the pathogenesis of coronary atherosclerosis. Several studies have shown that the DD genotype of the insertion-deletion (I-D) polymorphism of the ACE, which converts angiotensin (Ang) I to the bioactive peptide Ang II, had higher incidence of cardiac hypertrophy,¹⁰ myocardial infarction,¹ and restenosis after percutaneous transluminal coronary angioplasty.¹¹ Since the ACE genotype is associated with plasma ACE activity,¹ Ang II may play an important role in this association with coronary heart disease.

Angiotensinogen is also an important protein as a substrate for renin to form Ang I and Ang II. Previous studies^{12 13 14 15} indicated that angiotensinogen had an active regulatory function in both circulating blood and local tissues under physiological and pathophysiological conditions. Kinetic analysis of the renin reaction showed that plasma Ang II production is sensitive to small changes in both renin and angiotensinogen concentrations in the circulation.¹⁵ Although the angiotensinogen gene is mainly produced in the liver, analysis of the distribution of angiotensinogen mRNA by molecular biological methods has shown that the angiotensinogen gene is expressed in many tissues, including those of the brain, spinal cord, aorta, kidney, adrenal gland, atria, spleen, and adipose tissue. As in plasma, angiotensinogen appears to play a role in regulating local Ang II production. A study¹⁶ of the kinetics of the renin reaction in tissue extracts showed that synthesis of Ang II depended on the local availability of angiotensinogen, and another study¹⁷ supported the idea that angiotensinogen is involved in local control of Ang II production. Although the angiotensinogen mRNA level was extremely low in ventricles of normal hearts, mRNA significantly increased in hypertrophied left ventricles in an in vivo model of pressure-overload cardiac hypertrophy,¹⁸ and stretching increased angiotensinogen mRNA expression in primary cultured cardiomyocytes in vitro.¹⁹ In models of heart failure, the levels of heart and kidney angiotensinogen mRNA were especially high.^{20 21}

In addition, balloon injury can activate angiotensinogen gene expression in the medial layer of the aorta, which suggests that angiotensinogen has a role in the myointimal proliferation that occurs after such injury.²² All these results suggest that angiotensinogen is profoundly involved in the cardiovascular diseases.

To clarify a role of gene mutation in the pathogenesis of diseases, we have previously performed associated studies that used restriction fragment length polymorphisms of ₂ adrenergic receptor gene²³ and I-D polymorphism of ACE in essential hypertension.²⁴ In this study, we used the same technique to see the association between coronary atherosclerosis and mutations of the angiotensinogen gene.

Recently, several molecular variants of the angiotensinogen gene have been reported, and one of the mutations (a/a) of the angiotensinogen gene that we examined has been reported to be associated with essential hypertension in Caucasians³ and Japanese^{4 5} and with preeclampsia.⁷ However, another study in Caucasians in the United Kingdom failed to show any correlation between this variant and hypertension.⁶ Patients with this mutation (a/a) have been reported to have a higher angiotensinogen concentration in circulating blood.³ Therefore, it is possible that the higher incidence of coronary atherosclerosis we observed in this study may be due to elevated blood pressure caused by the a/a genotype. However, since the incidence of hypertension among both the patients and the control subjects is similar in this study, we suggest that the a/a genotype of the angiotensinogen gene is an independent risk factor for coronary atherosclerosis. Interestingly, the present results are consistent with the recent preliminary report, which showed that the incidence of this a/a genotype of the angiotensinogen gene was significantly greater in the patients with myocardial infarction than in the control subjects.²⁵

In conclusion, we examined the association of the molecular variant of the human angiotensinogen gene with coronary atherosclerosis and found a positive relation between them. Although the implication of this allele difference in the angiotensinogen gene mutation is not known, Ang II may play an important role in the development of coronary atherosclerosis in the patients with this mutation of the angiotensinogen gene. Recently, we have studied the basal transcriptional mechanism of the angiotensinogen gene.^{26 27} Future studies will identify the molecular relation between the polymorphism of the angiotensinogen gene and the pathogenesis of coronary atherosclerosis.

	Acknowledgments

 
This study was supported by grants-in-aid 06274224, 05670956, 05454275, and 4512 for Scientific Research from the Ministry of Education, Science and Culture, Japan, and a grant from the Kihara Memorial Yokohama Foundation for Life Science promotion and Yokohama Foundation for Advancement of Medical Science. Dr Kouichi Tamura is supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.

Received November 15, 1994; revision received December 2, 1994; accepted December 31, 1994.

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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 Ishigami, T. Articles by Ishii, M. Search for Related Content PubMed PubMed Citation Articles by Ishigami, T. Articles by Ishii, M.