© 1996 American Heart Association, Inc.
Articles |
Genotype Distribution of Angiotensin-Converting Enzyme Polymorphism in Australian Healthy and Coronary Populations and Relevance to Myocardial Infarction and Coronary Artery Disease
From the Department of Cardiovascular Medicine, University of New South Wales, Prince Henry/Prince of Wales Hospitals, Sydney, Australia.
Correspondence to Prof David Wilcken, Department of Cardiovascular Medicine, Clinical Sciences Building, Prince Henry Hospital, Little Bay, NSW 2036, Australia. E-mail x.l.wang@unsw.edu.au.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract Angiotensin-converting enzyme is a key component of the renin-angiotensin system that plays an important role in cardiovascular regulation. An association between the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and increased coronary risk has been found in some studies but not in others. To explore this further in an Australian white population, we compared the ACE genotype distribution in 550 patients aged 37 to 65 years with coronary artery disease documented by angiography with the genotype distribution in 404 healthy school children aged 6 to 13 years. We also explored associations in the patients between the angiotensin-converting enzyme I/D polymorphism and a history of myocardial infarction and coronary artery disease severity assessed by the number of major coronary arteries with more than 50% luminal obstructions and by the Green Lane coronary score. The frequencies of the angiotensin-converting enzyme genotype in the coronary artery disease patients were 0.236 for I/I, 0.395 for I/D, and 0.369 for D/D genotypes. This distribution with an excess of the D/D genotype was significantly different (
2=23.69,
P<.0001) from that in the school children, in whom the
genotype distribution was in Hardy-Weinberg equilibrium (I/I,
0.21; I/D, 0.54; D/D, 0.25). There was also a significant excess of D/D
genotype among patients with a history of myocardial infarction
(2=9.42, P=.009), and there was the
same D/D excess in the subgroup of children (n=60) with two or more
grandparents who had had coronary artery disease. We found no
associations between the angiotensin-converting enzyme
polymorphism and the number of significantly stenosed
coronary arteries (2=2.069,
P=.91). We conclude that the D/D genotype is a
significant predictor for coronary artery disease events in the
Australian white population but is not a marker for angiographically
assessed coronary artery disease severity. The
angiotensin-converting enzyme
genotype–associated increased risk for coronary
events may be mediated more by angiotensin II–induced
coronary vasoconstriction than by an increase in
injury-related smooth muscle cell proliferation in the
coronary vasculature.
Key Words: ACE I/D polymorphism • myocardial infarction • coronary artery disease, severity • renin-angiotensin system
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The renin-angiotensin system is involved in many aspects of cardiovascular regulation, including sodium homeostasis, cardiovascular remodeling, and maintenance of vascular tone,1 2 and ACE is a key component of it. The inactive angiotensin I is converted in vivo by ACE into the potent vasoconstrictor angiotensin II. An I/D polymorphism at intron 16 of the ACE gene has been identified and shown to explain up to 50% of the variance in circulating ACE activity, the D/D genotype being associated with higher circulating levels.3
In 1992, Cambien et al4 first reported an association of the ACE D/D genotype with MI survivors and particularly among those at `low` risk according to conventional risk factors. Several other groups have explored a possible relationship with CAD since then. Most retrospective studies supported the initial findings that the D/D genotype was more frequent in MI survivors and in cases of fatal MI and sudden cardiac death.5 6 7 8 Our own studies9 and those of Tiret et al10 and Bohn et al11 also identified an excess of the D allele in individuals with a positive family history of CAD in either first- or second-degree relatives. However, the recent large prospective American physician's study showed no association between ACE I/D polymorphism and the prevalence of MI or ischemic heart disease.12 Furthermore, Ludwig et al13 have reported an association with MI but observed no relationship between the polymorphism and the development of coronary stenosis in the same patient population. Sanmani et al14 also found no association between the ACE polymorphism and restenosis after coronary angioplasty.
In view of these conflicting findings obtained in different patient population groups and the possibility of a population-specific effect in relation to the ACE I/D polymorphism, we sought to explore two questions relevant to an Australian white population in the present study. The first is whether the genotype distribution of the ACE I/D polymorphism is different in healthy and coronary white Australian subjects. The second is whether there is an association between the polymorphism and the occurrence of MI and severity of CAD.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The healthy population was a previously reported group of 404 school children of approximately equal numbers of boys and girls aged 6 to 13 years who were part of a family heart health education program.9 15 All children were considered to be healthy by parents and teachers. After prior parental consent they were selected solely on the basis of ethnicity, in that all were white.9 Capillary blood samples were obtained by finger prick and spotted onto filter paper and stored at -70°C as previously described.9
The patients were whites aged 65 years or younger, both men and women, consecutively referred to the Eastern Heart Clinic at Prince Henry Hospital for coronary angiography over a 16-month period in 1994 and 1995. These patients were referred by cardiologists from outpatient clinics of local hospitals and from medical centers for assessment because of a suspected or confirmed clinical diagnosis of ischemic heart disease for determination of subsequent management. We excluded from analysis only patients shown to have significant left main disease (>50% luminal obstruction), because it was difficult to categorize this small proportion of the total (5%) within the classification system we used (see below).
Written consent was obtained from all parents of the children in the healthy population and from every patient after a full explanation of the study, which was approved by the Ethics Committee of the University of New South Wales.
A 4-mL venous blood sample was drawn into an EDTA sample tube in the patients before the angiogram after at least a 6-hour fast. The blood sample was centrifuged within 2 hours, and plasma and cellular components were stored separately at -70°C until analysis.
DNA Analysis for the Detection of ACE I/D
Polymorphism
DNA was extracted from the frozen cellular blood
component by a
salting-out method adapted from that described by Miller et
al16 for whole frozen blood. The extracted DNA was stored
at 4°C until analysis. ACE I/D polymorphism was
determined from the protocol of Badenhop et al9 and Rigat
et al17 with Taq polymerase (Boehringer
Mannheim) and a thermal cycler (Hybaid). The reaction included 5%
dimethyl sulfoxide to ensure that the I allele was amplified in all
heterozygotes.18 Any one person is either an I/I
homozygote, an I/D compound heterozygote, or a D/D homozygote for this
polymorphism.
Lipoprotein Analysis
TC, HDL-C, and triglyceride levels were
measured in
the patients by the hospital's clinical chemistry department with
standard enzymatic methods. LDL-C levels were calculated by the
Friedewald formula.
Documentation of CAD Severity
The severity of coronary
stenosis was determined
by the number of significantly stenosed coronary arteries as
follows. Angiograms were assessed by two cardiologists who were unaware
that the patients were to be included in the study. Each angiogram was
classified as revealing either no coronary lesion with more
than 50% luminal stenosis or one, two, or three major
epicardial coronary arteries with more than 50% luminal
obstructions. We also used the Green Lane coronary scoring
system, which provides a numerical value for lesion severity and takes
account of the amount of myocardium supplied by an affected
vessel; the maximum score is 15.
Documentation of Other Relevant Variables
The relevant
history was obtained for each patient with a
questionnaire, with standardized choices of answers to be ticked during
the interview. We recorded the presence or absence (yes/no) of a
history of MI, hypertension requiring treatment, diabetes, and angina
pectoris. Where these disorders were answered as positive, the
patient's medical records were consulted to confirm the diagnosis
of MI based on standard criteria (clinical manifestation, abnormal
enzymology, and electrocardiographic changes at the time of diagnosis).
A "don't know" box was also included for those patients not
clear about aspects of their medical history that were also unavailable
from the patient's file. Current medications were recorded, in
particular the use of lipid-lowering drugs. The presence or absence
of CAD among first-degree relatives (parents and siblings) and the
age of first onset were recorded for a quantitative assessment of
family history of premature CAD. We recorded the presence and
severity of angina according to whether each patient was experiencing
no angina, stable angina, or unstable angina before and during the
current hospitalization. All those classified as having unstable angina
had an increase in pain frequency as well as rest pain. The lifetime
smoking dose in pack-years was recorded as described
previously.19
Statistical Analysis
We determined whether the distribution
of genotypes was
in Hardy-Weinberg equilibrium by 2
analysis as described by Emery.20 The frequencies
of the alleles and genotypes among different subgroups were
compared by 2 test. We used a conditional
logistic regression analysis in which either a history of MI or
the number of significantly diseased vessels was the dependent
variable and assessed the independent effect of ACE
genotype while other measured variables were entered as
independent variables. The categorical variables in the
logistic analysis were coded so that the presence of diabetes,
hypertension, family history of CAD, and use of lipid-lowering
drugs were coded 1 and the absence of these disorders and nonlipid drug
users as 0. Since there were only 2 patients with "don't
know"
answers about family history, 2 about diabetes and hypertension, and 1
about history of MI, the "don't know" was simply coded as a
missing value and excluded from the analysis.
To compare our findings
with those reported by
others,4 5 6 7 8
we also conducted our 2 analysis in
low-risk subgroups. These were identified with reference to age
(
55 years for men and 60 for women), TC/HDL-C ratio (<5.0), BMI
(<27 kg/m2), and smoking history (nonsmokers). We used the
TC/HDL-C ratio instead of other lipid variables because it was the
strongest lipid predictor for CAD severity in this patient
population.19 The median BMI value in the patient
population was 27 kg/m2. To stratify patients according to
age, we used quartiles of the patient population for the
analysis. The 25th, 50th, and 75th percentiles were 53, 57, and
60 years.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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The demographic information for the 550 patients is shown in Table 1
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Genotypes in the Patients and Healthy School
Children
Although the distribution of the ACE genotype in the
school children was in Hardy-Weinberg equilibrium, as we showed
previously,9 in the 550 patients it was not
(2=23.69, P<.0001). In the patients
the expected and observed numbers of cases for the I/I genotype
were 104.4 and 130 (23.6%), for the I/D genotype 272.2 and 217
(39.5%), and for the D/D genotype 177.5 and 203 (36.9%). The
distribution pattern was virtually the same after patients with
angiographically normal coronary arteries (n=103) were excluded
(I/I, 106 [23.7%]; I/D, 179 [40.0%]; and D/D, 162
[36.2%]).
The frequency distribution of the genotypes was not different
between men and women, although the D allele frequency was slightly
higher among women (0.588) than men (0.557). The D allele frequency
for all patients was 0.566.
The frequency distribution of D/D genotypes
among all patients
who had reported having had an MI tended to be higher
(2=3.00, P=.22). After patients with
angiographically normal coronary arteries were excluded, there
was a significant excess of the D/D genotype among patients
with a history of MI (n=84, 40.4%) compared with those without
(n=78,
32.6%; 2=6.73, P=.027). This
relationship was even stronger among patients with one or more
significantly diseased (>50% luminal stenosis) vessels and a
history of MI (2=9.42, P=.009; Table
2). This significant association between the D/D
genotype and MI remained statistically significant
(r=.09, P=.02) in a logistic linear regression
analysis after controlling for all other categorical
variables (sex, number of significantly diseased vessels, diabetes,
hypertension requiring treatment, family history of CAD) and
quantitative variables (age, TC, HDL-C, LDL-C,
triglyceride, lifetime smoking dose, lipoprotein[a]).
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There
was a significant excess of the D/D genotype among the
patients compared with the distribution documented in the 404 school
children (Table 3). This difference was also true when
the comparison was only among those with one or more significantly
diseased (>50% luminal stenosis) vessels. However, as also
shown in Table 3, the frequency of the D/D genotype among those
children who had two or more grandparents with a positive CAD history
was the same as that in the CAD patients.
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ACE I/D Polymorphism and CAD Severity
We found no
statistically significant association between the ACE
I/D polymorphism and the number of significantly diseased vessels
in the patients, either in all patients or in men and women separately
(Table 4). The D allele frequencies in patients with
zero, one, two, or three significantly diseased vessels were 0.578
(0.556 for men and 0.598 for women), 0.569 (0.561 for men and 0.592 for
women), 0.553 (0.565 for men and 0.636 for women), and 0.563 (0.576 for
men and 0.500 for women), respectively (2=2.069,
P=.85). This lack of significant association was further
confirmed in a logistic regression analysis in which age, sex,
presence of diabetes, hypertension requiring treatment, angina, history
of MI, usage of lipid-lowering drugs and adrenergic
ß-blockers, TC/HDL-C ratio, BMI, and lifetime smoking dose were
controlled. The coronary scores for patients with the I/I
(5.44±0.4), I/D (4.92±0.3), and D/D (5.46±0.3) genotypes
were also not different (F=0.876, P=.42).
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In the
low-risk subgroup analysis, we cannot reject the
null hypothesis that the ACE polymorphism and severity of
coronary stenosis are independent. As shown in Table 5, the
distribution of ACE genotypes among men
aged 55 years or younger and women aged 60 years or younger with
different numbers of significantly diseased vessels was not different.
The same result was observed in the age categories stratified by the
population quartiles. There was also no statistically significant
association among low-risk groups identified according to the
TC/HDL-C ratio (lower than 5.0), absence of smoking, or BMI less than
27 kg/m2 (the 50th percentile of the patient population) or
among those with no hypertension, no diabetes, no history of MI, or no
angina. In fact, the frequency of the D/D genotype remained
virtually constant among patients with different numbers of diseased
vessels.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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We believe that the two populations we studied are genetically representative, first of the normal white population of Sydney, Australia, of school children, and second of coronary patients in that subgroup of the Sydney white population aged 65 years and younger who are judged by cardiologists to require coronary angiography for the diagnosis and management of CAD. Thus, the key finding of our study—that the distribution of the ACE I/D polymorphism is very different in the healthy and coronary populations, with a highly significant increase in the D/D genotype in the latter—constitutes further evidence for the relevance of the D/D genotype to CAD in white Australians. The second finding of a strong association between the presence of the D/D genotype and a history of MI in patients with angiographically demonstrated significant CAD adds further support to the original observation made by Cambien and colleagues.4 Our further finding of no statistically significant association between ACE genotype and the severity of CAD is in accordance with the recent observations of Ludwig and associates13 ; they found no association with development of coronary stenosis but a definite one with occurrence of MI.
While all these observations raise interesting questions about mechanisms, the association between genotype and CAD emerges clearly in our population. This is further supported by our finding of a D/D genotype excess in that subset of children with two or more grandparents who had coronary events. This excess was the same as the one we identified in the coronary patients. The fact that these associations have not been found in some other populations, particularly in the recent study of American physicians,12 who probably represent a low-risk group, may indicate that D/D genotype–associated coronary risk is population specific.
Despite the associations with coronary risk that we
demonstrated, the D/D genotype distribution was virtually the
same in the groups of patients with coronary syndromes and no
or mild CAD and in those with single, double, and triple vessel disease
(Table 4
). Nor was there an association with the coronary
score. A lack of this statistically significant association was also
seen among low-risk patients identified by age, TC/HDL-C ratio,
BMI, or smoking status. The older patients tended to have more
significantly diseased vessels, but the ACE genotype was still
not associated with CAD severity after controlling for age as a
quantitative or stratification variable. Furthermore, the frequency
of the D allele was not different in different age quartiles or in
men younger than 55 or women younger than 60 years. Although these
findings are supported by those of Ludwig and
colleagues,13 it is also relevant that Sanmani et
al14 found no association between ACE I/D polymorphism
and the development of restenosis after angioplasty in 233
patients.
All these findings would be consistent with ACE genotype–associated cardiovascular risk being more relevant to angiotensin II–induced coronary vasoconstriction than to any enhancing effects on smooth muscle cell proliferation. This could contribute to the association of the genotype with the occurrence of fatal and nonfatal MI, sudden cardiac death, and positive family history of coronary events5 21 and to associations with dilated cardiomyopathy7 and sudden death in families with hypertrophic cardiomyopathy.22 It could also be consistent with beneficial effects of ACE inhibitors in reducing the incidence and death from MI documented in drug trials.23
In conclusion, our study shows that there is a highly significant excess of the D/D genotype in Australian white patients with established CAD and that this is also associated with an increased risk of MI. We found no evidence for a relationship between the D/D genotype and the severity of CAD documented by angiography.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the National Health and Medical Research Council of Australia. We wish to thank Dr Bridget Wilcken for reviewing the manuscript; Lily Fenech, Shelly Brown, Steven Brouwer, Dr Greg Cranny, and all nurses in the Eastern Heart Clinic for their assistance in clinical data collection; A.S. Sim and Dr Jun Wang for their laboratory assistance; and J. Kessey for the data entry. We are also most grateful to the cardiologists in the department for allowing us to study their patients.
Received August 22, 1995; accepted October 30, 1995.
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References |
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