(Hypertension. 1997;30:574.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Gene Polymorphism Adds Risk for the Severity of Coronary Atherosclerosis in Smokers
From the Second Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, 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.
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Abstract |
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Abstract To investigate the relation between the angiotensin-converting enzyme (ACE) gene polymorphism and acute coronary syndromes with respect to environmental factors, we analyzed the association of genotype with the coronary angiographic findings of patients with acute myocardial infarction or unstable angina pectoris, and we examined the linkage of each genotype with established risk factors for coronary artery disease. We determined the ACE genotype in 152 Japanese patients with acute coronary syndromes and 399 healthy individuals. The genotype distributions were not different between the two groups (P=.74,
2 test). In the former group, coronary
angiograms were evaluated by criteria based on the number of diseased
vessels, the number of stenotic lesions (
50%), and the
relative abnormal arterial portion (extent index). Although
the number of stenotic lesions was higher in patients with the
DD genotype than in those with the ID or
II genotype (P=.006), there were no
differences in the number of diseased vessels or the extent index. When
only smokers were analyzed, the number of diseased vessels
(P=.032), number of stenotic lesions
(P=.003), and extent index (P=.019) were all
higher in patients with the DD genotype than in
those with the ID or II genotype. In
contrast, these differences in the respective parameters
did not exist in nonsmokers. The results indicate smoking-associated
effects of the ACE genotype on the severity of coronary
atherosclerosis.
Key Words: angiotensin • genes • coronary disease • smoking • atherosclerosis
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Introduction |
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Coronary artery disease directly influences mortality in both Japan and the West and leads to
160 000 deaths every year in Japan. Among the factors
that contribute to the development of CAD are hypertension,
hyperlipidemia, diabetes mellitus, smoking, and a
patient’s genetic background. Many treatments have aimed to reduce the
environmental risk factors that lead to CAD; however, little is known
about its pattern of inheritance. The renin-angiotensin system plays important roles in the maintenance of body fluid and sodium balance, modulation of blood pressure, and cardiovascular remodeling.1 2 3 ACE, a component of the renin-angiotensin system, hydrolyzes angiotensin I to generate the pressor peptide angiotensin II. ACE is also involved in the kinin-kallikrein system, where it inactivates the vasodilator peptide bradykinin. Recently, an insertion/deletion (I/D) polymorphism (the presence or absence of a 287-bp Alu repeat sequence) has been identified in intron 16 of the human ACE gene.4 The I/D polymorphism of the ACE gene influences the serum levels of ACE activity.4 Despite several reports of an association between the ACE DD genotype and an increased risk of cardiovascular diseases,5 6 7 8 9 other groups failed to confirm the association.10 11 12
Although the relationship of the ACE I/D genotype to the development of CAD is unclear, genetic factors that predispose to CAD have been suggested to interact with environmental risk factors, such as smoking.13 Indeed, recent reports indicated that the ecNOS4a polymorphism is a smoking-dependent risk factor14 on the development of coronary atherosclerosis and that ACE I/D polymorphism relates to coronary artery spasm, especially in smokers.15
To investigate whether the ACE gene I/D polymorphism is associated with increased severity of coronary atherosclerosis in relation to the established risk factors for CAD, we evaluated the angiographic severity of coronary atherosclerosis, the ACE I/D gene polymorphism, and established risk factors in patients with symptomatic CAD.
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Methods |
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Study Population
Patients With CAD
We recruited 156 consecutive Japanese patients at first presentation of acute myocardial infarction or unstable angina pectoris who were admitted to the Department of the Coronary Care Unit of Yokohama City University Critical Care and Emergency Center. All patients gave their informed consent to supply peripheral blood for DNA analysis to investigate the genetic basis of CAD. We failed to obtain DNA from 4 subjects; thus, the final study population comprised 152 patients.
Control Subjects
The healthy control individuals had no symptom of CAD and normal
electrocardiogram (220 males; mean age, 57 years; 179
females; mean age, 58 years). All subjects gave their informed consent
to be enrolled in this study.
Angiographic Criteria
In the evaluation of coronary angiograms, conventional
criteria such as the number of diseased vessels with stenoses
75% and the number of lesions with stenoses 50% provide
limited information about the overall degree of coronary
atherosclerosis. In contrast, the extent index proposed
by Bogaty et al16 allows longitudinal estimation of the
extent of atherosclerosis on coronary
angiograms and thereby provides a more realistic picture of the
severity of coronary atherosclerosis. These
three variables were therefore analyzed. The degree of
narrowing can be estimated by counting the numbers of diseased vessels
and of stenoses, and the proportion of each coronary
segment that appears abnormal can be assessed by the extent index. The
extent index was evaluated visually by assigning a score of 0 to 3 per
segment of the coronary arterial tree. A segment
was scored 0 if it appeared normal; 1 if <10% of its length appeared
abnormal; 2 if 10% to <50% of its length appeared abnormal; and 3 if
50% of its length appeared abnormal. The extent score was expressed
as the total score of the 15 segments. The American Heart Association
classification was used to divide angiograms into segments. The extent
index was calculated by dividing the extent score by the number of
segments to adjust for individual variability. Thus, the extent index
could range from 0 to 3. Angiograms were evaluated by two observers who
were blinded to all clinical data and to ACE genotype. When
these observers differed, a third observer intervened.
Risk Factor Criteria
Established risk factors were evaluated on the basis of
peripheral blood analysis, direct interview of the
patients, and hospital records, if available. Subjects who smoked
>15 cigarettes a day for at least 2 years before angiography were
defined as smokers, while other subjects were classified as nonsmokers.
Hypertensive patients were defined as those in whom hypertension had
been diagnosed previously or those who had a history of
antihypertensive therapy. Diabetes mellitus was defined as a prior
diagnosis of the disease, a history of antidiabetic medication, or
plasma fasting glucose levels 7.8 mmol/L on two or more
occasions. Serum total cholesterol, HDL
cholesterol, and triglyceride levels were
measured by enzymatic assay in blood specimens obtained in the morning
after a 12-hour fast. Apolipoproteins were measured by turbidimetric
immunoassay.17 ACE activity was quantified by
Kasahara’s method18 and PRA by a standard
radioimmunoassay technique.19 Blood specimens were
obtained from myocardial infarction patients at least 1 week after
infarction. Patients receiving ACE inhibitor were excluded
from analysis. ACE activity was measured in 78 of 152 and PRA
in 73 of 152 patients.
DNA Analysis
Blood samples were drawn into heparinized tubes, and the
leukocytes were separated. Genomic DNA was isolated from
peripheral leukocytes using a Nucleon Extraction Kit. The
ACE genotype was determined by the PCR technique according to
the method of Rigat et al20 with minor modifications. PCR
products were analyzed by 1.6% agarose gel electrophoresis
and visualized with ethidium bromide staining for allele
identification.21 A 490-bp fragment (in the presence of
the insertion allele) and a 190-bp fragment (in the absence of the
insertion allele) were identified. We confirmed the accuracy of the
genotyping results in the DD homozygotes by using an
insertion-specific primer, which proved to be the most reliable PCR
strategy to maximize precise genotyping.22
Statistical Analysis
All statistical analyses were conducted with use of the
SPSS statistical package version 6.1. Data are expressed as mean±SEM.
The 2 test was used to compare genotype
frequency between groups. Departures from Hardy-Weinberg expectations
were tested with 2 analysis.
Distributions of sex (male or female), smoking status, presence of
family history of CAD, hypertension, and diabetes mellitus among the
three genotype groups were analyzed by construction of
3x2 contingency tables and 2 analyses.
Distributions of variables were checked by the Kolmogorov-Smirnov
goodness-of-fit test. Since the number of stenoses was not
distributed normally, statistical tests were performed on square
root–transformed stenoses values. Differences between the
means of two genotype groups were evaluated by unpaired
Student’s two-tailed t tests, and those of three
genotype groups were evaluated by ANOVA with the Bonferroni
correction applied for multiple comparisons. The severity of
coronary angiographic findings with respect to
genotypes was analyzed by ANCOVA and adjusted by age,
sex (male=0, female=1), and BMI (kg/m2). A value of
P<.05 was considered to indicate statistical
significance.
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Results |
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The 152 patients consisted of 126 with acute myocardial infarction and 26 with unstable angina pectoris. The genotype distribution in the patients group was 25 DD (16.4%), 69 ID (45.4%), and 58 II (38.2%). In the control group, the genotype distribution was 59 DD (14.8%), 174 ID (43.6%), and 166 II (41.6%). The genotype distributions were not different between patients and the control group (P=.74). The frequencies of each genotype were compatible with the Hardy-Weinberg equilibrium distribution in either group.
We then analyzed the clinical variables and angiographic
findings of patient group subdivided by genotype to determine
whether genotype had any influence on the severity of
coronary atherosclerosis. The characteristics
of the 152 patients are summarized in Table 1. No differences were detected between
groups in age, sex, BMI, total cholesterol, HDL
cholesterol, triglyceride, apolipoprotein B,
uric acid, frequency of hypertension, frequency of diabetes mellitus,
or family history of CAD. The frequencies of smokers among the patients
with the DD, ID, and II
genotypes were 44%, 59%, and 72%, respectively. There was a
lower frequency of heavy smokers among patients with the DD
genotype (2=6.3, P=.043).
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The serum levels of ACE activity were significantly elevated in the DD genotype group compared with the ID or II genotype group (P=.001), confirming an association between the ACE gene polymorphism and the serum levels of ACE activity, as reported previously.4
Comparisons of Severity of CAD Among ACE Genotype
Subgroups
The three genotypes are compared with respect to
diseased vessels, stenoses, and extent index in Table 2. Although the patients with the
DD genotype had more stenoses than those
with the ID or II genotype when we
compared three indexes in the 152 patients (smokers and nonsmokers),
there was no significant difference in the number of diseased vessels
or the extent index among genotypes. To assess the interaction
between ACE I/D polymorphism and other
established coronary risk factors, we divided the patients into
two groups according to sex (male or female), obesity (BMI 26
kg/m2 or not), hyperlipidemia (total
cholesterol 5.7 mmol/L or not), smoking
status, hypertension (with or without), and diabetes mellitus (with or
without). Besides smoking history, we found no interaction between ACE
I/D polymorphism and any other
coronary risk factor. Therefore, we divided the subjects into
two groups according to their smoking history and evaluated the
coronary angiograms in each ACE genotype subgroup.
Among smokers, the number of diseased vessels was significantly higher
in patients with the DD genotype than in those with
either the ID or the II genotype (Table 2). When we compared the numbers of stenoses among the three
groups, patients with the DD genotype had more
stenoses than those with the ID or II
genotype (Table 2). Similar results were obtained for extent
index. Patients with the DD genotype had a higher
extent index than those with the ID or II
genotype (Table 2). No significant difference was found between
the ID and II genotype in the number of
diseased vessels, the number of stenoses, or the extent index.
On the other hand, when we evaluated coronary angiograms in
nonsmokers, the findings were obviously different from those in
smokers. No significant differences were noted in any variable
among the three genotypes.
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Clinical Variables in Smokers and Nonsmokers
Table 3 compares clinical
characteristics and the severity of coronary angiograms between
smokers and nonsmokers. Smokers were younger than nonsmokers (60.8±1.1
and 67.4±1.3 years, respectively, P=.0002), and the
proportion of males was higher among smokers than nonsmokers (91.4%
and 55.9%, respectively, 2=23.2,
P<.0001). Smokers had significantly higher levels of PRA
than nonsmokers (P=.045). Apart from these, there were no
other differences between smokers and nonsmokers in any other
characteristics shown in Table 3. When we compared the number of
diseased vessels, the number of stenoses, and the extent index
between smokers and nonsmokers, no differences were found even after
adjustment for sex and age.
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Independent Effects of ACE Gene on the Severity of CAD
The above observations suggest that the genotype of the
ACE gene may affect the development of CAD in smokers. To assess the
independent influence of the DD genotype on the
severity of CAD, ANCOVA analyses were performed in which the
genotype of the ACE gene was included as a factor; age, sex
(male=0, female=1), and BMI as covariables; and the severity of CAD
(number of diseased vessels, number of stenoses, and extent
index) as dependent variables (Table 4). Patients with the DD
genotype showed more stenoses than those with the
ID or II genotype in the whole population
(P=.009). No difference was observed in the number of
vessels or the extent index. However, when only smokers were
analyzed, patients with the DD genotype
showed more diseased vessels (P=.04), more stenoses
(P=.009), and a higher extent index (P=.015). On
the contrary, no difference between genotypes was found in
nonsmokers.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we investigated the relationship between the ACE DD genotype and conventional risk factors in the development of coronary atherosclerosis. Several studies have shown a high prevalence of the DD genotype among patients with cardiovascular disorders, such as myocardial infarction5 or CAD.6 7 However, other groups found no association between the DD genotype and CAD.10 One possible reason for this discrepancy is differences in genetic background in the sample examined. Another is differences in the criteria used to select patients or control subjects.10 In the present investigation, we conducted a case-control study and observed no association between I/D polymorphism of the ACE gene and acute coronary syndromes. However, we found that the ACE DD genotype was associated with increased severity of CAD, as indicated by the degree and longitudinal extent of coronary angiographic narrowing in smokers only. Thus, gene-environmental interactions could also be a possible reason for the discrepancy.
The renin-angiotensin system may play an important role in the pathogenesis of atherosclerosis. ACE, which is a major component of the renin-angiotensin system, is a membrane-bound ectoenzyme expressed in all vascular beds and the parenchyma of some tissues. Several studies have shown that plasma levels of ACE are elevated in subjects with the ACE DD genotype,4 23 which is consistent with the present results. A finding of elevated cardiac ACE activity in such persons24 suggests that tissue as well as plasma ACE activity is elevated in persons with the DD genotype. Furthermore, a recent study showed that the pressor response to angiotensin I infusion was greater in normotensive subjects with the DD genotype than in those with the II genotype,25 although another group failed to show such an effect when they infused a priming intravenous dose of the renin inhibitor remikiren to suppress endogenous angiotensin I and angiotensin II production.26 Increased plasma levels of ACE in DD subjects might increase angiotensin II production by accelerating conversion from angiotensin I to angiotensin II. Increased levels of ACE in tissue vascular beds might also increase angiotensin II production in the vasculature, which over many years might lead to atherosclerosis.27
Smoking has been implicated in the pathogenesis of numerous conditions, including cardiovascular disease. Of particular concern is the increasing number of young smokers. Although smoking is associated with coronary atherosclerosis,28 29 the link between smoking and atherosclerosis has not been fully elucidated. Furthermore, the effects of smoking on disease show enormous individual variability, due perhaps in large part to genetic factors. Recently, the ecNOS4a polymorphism has been reported to be a smoking-dependent risk factor for atherosclerosis.14 Furthermore, synergistic effects of smoking and ACE DD genotype on vasospastic angina pectoris have been reported.15 Thus, we speculate that the ACE DD genotype also contributes to genetic variations in disease susceptibility, although the mechanisms by which interactions between the DD genotype and smoking promote coronary atherosclerosis remain unclear.
Since angiotensinogen, renin, and ACE are thought to play important roles in the regulation of the renin- angiotensin system through the systemic and local production of angiotensin II,27 30 31 elevations of PRA, ACE activity, or both might promote the development of cardiovascular diseases. In the present study, PRA was greater in smokers than nonsmokers, which is consistent with a previous report,32 and ACE activity was greater in the DD genotype than the other genotypes, also in accord with previous reports.4 23 However, PRA alone did not correlate with the severity of coronary atherosclerosis, including vessels (r=-.094, P=.43), stenosis (r=-.064, P=.59), and extent index (r=-.123, P=.30). Thus, although it is too early to draw definite conclusions about the mechanism of the increased severity of coronary atherosclerosis in the smokers with the DD genotype, we speculate that elevated PRA together with (probably) elevated tissue ACE activity24 may accelerate angiotensin II production in the vasculature and the development of atherosclerosis.
More than 15 studies have addressed the association between the ACE genotype and CAD or myocardial infarction.33 However, the results have not been consistent.33 34 The present study suggests that one possible reason for the discrepancy could be different frequencies of smokers in each study. In addition, when the effects of age, sex, and BMI were considered, coronary atherosclerosis, as indicated by angiographic narrowing and longitudinal extent, was significantly more severe in smokers with the DD genotype than in nonsmokers with the DD genotype (data not shown).
Our study had several limitations. First, although ANCOVA was performed to adjust for differences in age, sex, and BMI, our analysis might have been insufficient because female smokers with the DD genotype were not included in our study population. However, our results should still be valid because we obtained similar results when only male subjects (n=118) were analyzed. Second, because of the small number of patients, we defined subjects who smoked >15 cigarettes a day for at least 2 years before angiography as smokers. Since we obtained similar results when we defined smokers as subjects who smoked >5 cigarettes or 1 cigarette a day, the relationship between smoking dose and severity of coronary atherosclerosis should be examined in a larger study. A third limitation was that we evaluated coronary angiograms only at the patients’ first presentation of acute coronary syndromes. A larger, more general population should be examined to confirm the pathologic interaction between smoking habits and the ACE genotype.
In summary, the genotype distributions were not different between diseased and control populations. However, we found the smoking-associated effects of the I/D polymorphism of the ACE gene in the severity of coronary atherosclerosis in Japanese patients with acute coronary syndromes. These smoking-associated effects of the ACE DD genotype suggest that heritable and environmental factors interact and lead to the manifestations of CAD. From the standpoint of prevention, young persons screened for the ACE I/D gene polymorphism and found to bear the DD genotype should be advised by physicians that they are at particularly high risk for CAD and that continued smoking could significantly shorten their lives.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants from the Ministry of Education, Science, and Culture of Japan (K.T., S.U., M.I.), the Kanagawa Academy of Science and Technology Research (T.I.), and the Uehara Memorial Foundation (K.T., S.U.). Dr Kouichi Tamura is supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists. We thank Dr Shinichirou Ueda for his help and advice. We would like to express our gratitude to Dr Shunsaku Mizushima and Dr Hirokazu Kimura, Department of Public Health, Yokohama City University, for statistical advice. We also thank Dr Mitsugu Sugiyama, Dr Masami Kosuge, and the nursing staff at Yokohama City University Critical Care and Emergency Center for their kind support.
Received March 17, 1997; first decision April 15, 1997; accepted April 30, 1997.
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