© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Angiotensin-Converting Enzyme Gene Polymorphism and Carotid Wall Thickening in a Community Population
From the Sir Charles Gairdner Hospital Campus of the Heart Research Institute of Western Australia (B.M.M., M.N., P.L.T.), the Department of Clinical Biochemistry, PathCentre, QEII Medical Centre (J.P.B.), and the Department of Medicine, University of Western Australia (J.H.), Nedlands, Western Australia.
Correspondence to A/Prof Joseph Hung, University Department of Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia 6009. E-mail jhung{at}cyllene.uwa.edu.au
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Abstract |
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Abstract—The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of coronary heart disease, but whether it is a risk factor for underlying atherosclerosis remains unclear. Therefore, we examined to see whether the ACE gene deletion polymorphism was associated with carotid wall thickening and atherosclerotic plaque formation in a large randomly selected community population. A total of 1111 subjects, aged 27 to 77 years, with an equal male:female ratio and equal numbers in each age decile, were randomly selected from the Perth community population. Mean common carotid intima-medial wall thickness (IMT) and focal plaque formation were assessed by high-resolution B-mode ultrasound. The ACE gene I/D polymorphism was detected by PCR. The distribution of the ACE genotypes conformed to the Hardy-Weinberg equilibrium (DD, 31.0%; ID, 48.4%; and II, 20.6%). The D allele was strongly correlated in a codominant fashion with plasma ACE activity (rs=0.53, P<0.0001), and accounted for 33% of the total variance in circulating ACE activity. No significant differences among the ACE genotypes were found with respect to age, sex, and conventional risk variables, including a history of hypertension and vascular disease. The average mean IMT and prevalence of increased IMT and focal plaque were not significantly different among genotypes in the overall population or in the subset (n=852) who were conventionally low risk by Framingham coronary heart disease risk score. Logistic regression analysis selected age, systolic blood pressure, pack-years of smoking, LDL cholesterol level, waist/hip ratio, and history of hypertension, but not the D allele, as multivariate predictors of increased IMT and carotid plaque formation. We conclude that, although the ACE I/D polymorphism is strongly related to ACE activity, it is not a risk predictor of carotid wall thickening or focal plaque formation when examined in a large randomly selected community population.
Key Words: angiotensin-converting enzyme • genes • atherosclerosis • intima-medial thickness • ultrasonography
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Introduction |
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On the basis of the Etude Cas-Témoin de l'Infarctus du Myocarde study, Cambien et al1 first reported in 1992 that a deletion polymorphism in the gene for the angiotensin-converting enzyme (ACE) was more frequent in patients with myocardial infarction (MI) than controls, especially among subjects formerly considered to be at low risk (low body-mass index and low plasma levels of ApoB). Subsequent case–control studies have not always agreed with this finding, although a recent meta-analysis2 comprising 15 studies did support a significant (albeit weak) association between the ACE D allele and increased MI risk. In the same meta-analysis,2 it was highlighted that all the case–control studies could be influenced by a mortality selection bias as cases were recruited at some time (variable) after the incident MI, and there was also a suggested publication bias toward smaller studies with positive results. It is noteworthy that the only prospective study, conducted in almost 3600 North American male physicians, found that the D allele of the ACE gene conferred no appreciable increase in risk of MI or ischemic heart disease.3 Thus, it is still debated whether ACE insertion/deletion (I/D) gene polymorphism is associated with an increased cardiovascular risk.
The case for the ACE I/D polymorphism being a risk factor for coronary heart disease (CHD) would be stronger if it is shown that the D allele is associated with an increased risk of atherosclerosis. The mechanism(s) underlying such an association is unclear, but it is known that the level of circulating and probably tissue ACE activity are under strong genetic control.4 5 6 Higher circulating and tissue ACE activity is present in subjects with the D compared with I allele,4 5 6 although the I/D polymorphism is itself only a marker for the functional polymorphism that influences ACE levels. ACE catalyzes the conversion of angiotensin I to angiotensin II and the breakdown of bradykinin to kinin degradation products. Both angiotensin II and bradykinin are potent peptide hormones that play an important role in vascular wall homeostasis by opposing effects on vascular tone, vascular smooth muscle cell growth, and production of extracellular matrix.7 8 9 10 Thus, chronic exposure to high levels of circulating and tissue ACE may well predispose to vascular wall thickening and atherosclerosis.
The association between ACE I/D polymorphism and increased carotid intima-medial wall thickness (IMT) or carotid plaque formation has been examined in several relatively small and often selective population samples with heterogeneous findings.11 12 13 14 15 16 We therefore decided to test for the association of carotid IMT and ACE I/D polymorphism in the Perth Carotid Ultrasound Disease Assessment Study (CUDAS). The latter consisted of 1111 male and female subjects, aged 27 to 77 years, randomly selected from the Perth community population, all of whom had high-resolution bilateral B-mode carotid ultrasound examination and ACE I/D gene polymorphism determined as part of a detailed risk factor assessment.
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Methods |
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Subjects
Subjects were original participants in the 1989 Australian National Heart Foundation Perth Risk Factor Prevalence Survey.17 This was a random electoral roll survey of 2000 people from the Perth, Western Australia, metropolitan area, with equal numbers of males and females and equal numbers of subjects in each age decile between 20 and 70 years. Repeat electoral roll and death record matching in May 1995 established a current address for 1807 living subjects. All of these were invited to attend our study clinic between June 1995 and December 1996, and 1111 subjects (61% of those eligible) agreed to participate. Subjects who had previous carotid artery surgery were excluded. The present study population was predominantly white with 90% of participants recording Australasia as their country of birth. Their age-adjusted prevalence of risk factors was similar to that reported for the entire 1989 cohort.17 Written informed consent was obtained from all study participants. The study protocol was approved by the Institutional Ethics Committee of the University of Western Australia.
A self-administered questionnaire similar to that used by the 1989 Australian National Heart Foundation Risk Factor Prevalence Survey was used to record a history of hypertension, hyperlipidemia, diabetes, angina pectoris, MI, stroke, or a family history of premature-onset CHD by age 55 years in first-degree relatives.17 Smoking lifetime exposure by pack-years was calculated. Anthropomorphic measurements and the lower of 2 resting sitting blood pressures (BPs), measured with a mercury column manometer, were recorded by a trained research nurse.
Laboratory Measurements
In all subjects, a fasting venous blood sample was obtained.
Total cholesterol, HDL cholesterol, and
triglyceride levels were determined enzymatically with a
Hitachi 747 autoanalyzer. LDL cholesterol was
calculated with the method of Friedewald et al.18 Genomic
DNA was extracted by the salt/phenol/chloroform method from the cells
of the buffy coat. The I/D polymorphism of the ACE gene
was detected by using PCR according to the method of Rigat et
al.19 Misclassification of ID to
DD was checked by performing a second independent PCR
amplification of DD samples, using an insertion specific
primer20 Plasma ACE activity was determined by using
N-[3-(2 furyl)acryloyl]-L-phenylalanylglycylglycine
substrate21 and calibrated by the method of Buttery
and Gee.22
Carotid Ultrasound
Bilateral carotid B-mode ultrasound was performed by 2 trained
sonographers using a 7.5-MHz annular phased-array transducer on an
Interspec (Apogee) CX 200 ultrasound machine. Scans were performed
according to a standardized protocol similar to that used by Salonen et
al.23 The characteristic echo interfaces on the far wall
of the distal common carotid artery was optimized and recorded on
super VHS videotape along with an ECG lead for subsequent off-line
analysis. A thorough search of the distal common carotid,
carotid bulb, and internal and external carotid arteries was also made
to determine the presence of focal plaque. Plaque was defined as a
clearly identified area of focal increased thickness (
1 mm) of
the intima-media layer.
The IMT was defined as the distance between the characteristic echoes from the lumen-intima and media-adventitia interfaces.24 End-diastolic images were digitized and a semiautomated edge-detection software program used to identify leading-edge echo-interface points from the far wall of the distal 1 cm of the common carotid artery.25 Three end-diastolic images were analyzed from the right and left distal common carotid arteries at a site free of any discrete plaque, and measurements averaged to give the mean IMT. Repeat measurement of randomly selected scans revealed no significant variation in the IMT measurement obtained during any specific time period of the study. Quality control measures included repeat scans on a subset of 30 subjects on 2 separate occasions 7 to 10 days apart. The intraobserver coefficient of variability was 2.9% for sonographer 1 and 4.8% for sonographer 2. The interobserver coefficient of variability was 5.9%.
Statistical Analysis
Analysis was restricted to the 1106 subjects who
had complete data including ACE I/D polymorphism and
plasma ACE activity. Analysis was also performed on a
subpopulation of 852 subjects defined as low risk based on a Framingham
CHD risk score of <20.26 This predicted an average
CHD risk of <1.8% per year over 10 years. ANOVA was used to compare
mean values between groups and if overall significance was
demonstrated, intergroup differences were assessed by multiple range
testing. Frequencies were compared by 
2
analysis. Determinants of plasma ACE activity were assessed by
multiple linear regression. Carotid mean IMT was treated as a
continuous as well as a categorical variable with those above the
90th percentile of mean IMT (>0.8 mm) for the total cohort
classified as having increased IMT. The relation of continuous risk
factors with mean IMT was examined nonparametrically by
using the Spearman rank correlation. The association of ACE activity
and ACE genotype with thickened IMT or plaque was investigated
by means of stepwise logistic regression analysis, considering
potential confounding risk variables including age, sex, and other
conventional risk factors. Risk variables were entered into the
logistic regression analysis as the highest quartile versus
other quartiles. The genotype effect was examined according to
a dominant (DD/ID versus II), codominant
(DD versus ID versus II), or recessive
(DD versus ID/II) model. For
multivariate risk predictors, the adjusted odds ratios
are given with the 95% confidence intervals (CIs). Analysis
was performed with SAS statistical software.27
Statistical significance was taken as a 2-sided P value of
<0.05. Results are expressed as mean±SD values unless otherwise
stated.
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Results |
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In the total population, the frequency of the D allele was 55.2% and I allele 44.8%. The distribution of the genotypes conformed to the Hardy-Weinberg equilibrium (DD, 31.0%; ID, 48.4%; and II, 20.6%). The proportion of DD subjects did not change across age deciles from 27 to 77 years. No significant differences were found among the 3 genotypes with respect to sex, age, and conventional risk factors, including BP or a family history of premature CHD (Table 1
). Nor
did we observe a significant difference among genotypes in the
prevalence of a history of previous MI or stroke.
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By Spearman rank correlation, plasma ACE activity was strongly
associated with the ACE I/D polymorphism
(rs=0.53, P<0.0001). The ACE
genotype affected plasma ACE activity levels in a codominant
fashion with activity highest in DD, intermediate in
ID, and lowest in II subjects in the overall
population and the low-risk subpopulation (P<0.0001, ANOVA;
Table 2). The ACE genotype, male
sex, and history of hypertension were independent determinants of
plasma ACE activity (total R2=0.31,
P<0.0001). History of hypertension was negatively
correlated with plasma ACE activity, reflecting lower activity in those
treated with ACE inhibitors. In the 842 subjects (76% of
total population) without a history of hypertension, the
genotype alone accounted for 33% of the total variance in
measured ACE activity (R2=0.33,
P<0.0001).
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Among the ACE genotypes in the total population, there
were no significant differences in the mean carotid IMT and prevalence
of increased IMT or focal plaque (Table 2
). We calculated that
the present study had >80% power at an 
level of
0.05 to detect a 5% difference in mean IMT thickness or a 30%
difference in prevalence of focal plaque between the DD and
other genotypes. The 852 subjects comprising the low-risk
subpopulation had as expected a lower mean IMT than the rest of the
population (0.67±0.12 versus 0.83±0.15 mm,
P<0.0001), but again across the genotypes there
were no significant differences in the mean IMT and prevalence of
increased IMT or focal plaque (Table 2).
On Spearman rank correlation, all the conventional continuous
risk factors, but not plasma ACE activity or genotype, were
significantly associated with mean IMT, as shown in Table 3. Stepwise logistic regression
analysis selected, in order, age, systolic BP,
pack-years of smoking, LDL cholesterol level, waist/hip
ratio, and history of antihypertensive treatment as
multivariate predictors of thickened IMT in the total
population, as shown in Table 4. Sex was
no longer a significant predictor once other risk variables were
accounted for. For plaque, similar risk variables were selected
with additional risk predictors being a history of vascular disease and
diabetes mellitus (Table 4). The plasma ACE activity and the
D allele were not selected as predictors of thickened
IMT or plaque formation, whether the allele was entered as a
dominant, codominant, or recessive gene polymorphism. The adjusted
odds ratio for thickened IMT in subjects with the DD versus
ID/II genotypes was 0.9 (95% CI, 0.5 to 1.4); for
plaque it was 0.9 (95% CI, 0.6 to 1.5) (Table 4). There was
also no association of D allele with thickened IMT or
plaque in the conventional low-risk subpopulation, with similar
adjusted odds ratios and CIs as those estimated for the total
population.
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Discussion |
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Our study demonstrated that the ACE I/D polymorphism is a strong determinant of plasma ACE activity, or, more correctly, is in tight linkage disequilibrium with a functional polymorphism that strongly influences circulating as well as tissue enzyme activity.4 5 6 This elevation may lead to increased risk of atherosclerosis by modulating the opposing effects of angiotensin II and kinins on endothelial function, smooth muscle cell proliferation, and extracellular matrix production in the vessel wall.7 8 9 10 Thus, it is postulated that subjects with the D allele may show increased carotid wall thickness, which is thought to represent an early phase of diffuse atherosclerosis.24 28 However, in this present study of a large randomly selected community population, we could find no association of the D allele with carotid mean IMT, or the prevalence of thickened IMT and carotid plaque formation. We also found no association between ACE genotypes and carotid wall thickness when examined in a subpopulation at conventionally low risk based on the Framingham CHD risk score.
A recent meta-analysis2 that had included 15
studies supported a positive, although weak, association of the
D allele with increased MI risk. However, it was noted
that the study findings were heterogeneous, and that by
contrast to the smaller (usually) positive case–control studies, the
only large prospective study3 did not show any
increased MI risk with the D allele. It was believed
that these study differences could well have been explained in many
cases by an inadequate sample size, selection bias in patients or
controls, and differences in age, ethnicity, and environmental
background of populations studied.2 The same
limitations appear to apply to the small number of studies that have
examined the association of ACE I/D polymorphism with
carotid IMT, and reported similarly heterogeneous findings
(summarized in Table 5).11 12 13 14 15 16 Four of these
studies found a positive association,11 14 15 16 although
this was only after a quarter of subjects on drug treatment were
excluded from analysis in 1 small study11 and only
among nonsmokers in another study16 ; 2 other
studies12 13 showed no association of the D
allele with carotid wall thickening or disease despite that it
conferred an increased risk of lacunar stroke in 1
study.13 None of the studies were able to demonstrate
a relationship between the D allele and carotid plaque
or stenosis.
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The strength of the present study is that it was conducted in a
large, randomly selected, community population, which included an equal
male:female ratio, and subjects across a wide age range (27 to 77
years) with equal numbers in each age decile. The frequencies of the
D and I alleles in our mainly white
population are consistent with those reported in other similar
populations.2 There was not a decline in the
frequency of the DD genotype with increasing age, as
might be anticipated if it conferred an increased
cardiovascular risk. As expected, the major
conventional risk factors were found to be multivariate
predictors of mean IMT and carotid plaque formation (Table 4).
However, the D allele was not found to be associated
with either thickened IMT or carotid plaque formation, irrespective of
whether it was considered a dominant, codominant, or recessive gene
polymorphism. In fact, subjects with the DD versus other
genotypes had an adjusted odds ratio for increased IMT and
carotid plaque that was very near unity and with narrow CIs around this
estimate. Cambien et al1 made the original
observation that the DD genotype was particularly
associated with increased MI risk in those who were conventionally low
risk. However, we found no association of D allele with
increased IMT or carotid plaque in our subpopulation of subjects who
had a predicted low CHD risk based on the Framingham risk score. We
also found no difference in recorded systolic and
diastolic BPs or history of hypertension among the 3
genotypes. Further, we observed no difference in the prevalence
of a history of MI or stroke among the ACE genotypes, but it
should be emphasized that our present study did not have the power
to demonstrate or exclude an effect of ACE genotype on these
vascular events given their low prevalence in this randomly selected
community population.
Our study should not be regarded as necessarily excluding an involvement of the renin–angiotensin system in the progression of atherosclerosis, and there is increasing experimental and clinical evidence for the vascular benefits of ACE inhibitor treatment.9 29 30 However, the mechanism remains uncertain.31 A pathogenetic role for other genetic mutations affecting the renin–angiotensin system is also possible.31 However, this present study indicates that the ACE I/D polymorphism is not a useful marker of subjects at increased risk of atherosclerosis in a general community population.
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Acknowledgments |
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This study was supported by grants-in-aid from the National Heart Foundation of Australia (G 94P 4232) and Healthway, the Western Australian Health Promotion Foundation (to J.H., M.N., P.L.T., J.P.B.). We appreciate the technical assistance provided by Elsie Yu and Marcus Sommerville, Heart Research Institute, Sir Charles Gairdner Hospital, and Clive Hunt and Christine Chin, PathCentre, Queen Elizabeth II Medical Center.
Received September 17, 1998; accepted January 6, 1999.
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P. Jerrard-Dunne, H. S. Markus, D. A. Steckel, A. Buehler, S. von Kegler, and M. Sitzer Early Carotid Atherosclerosis and Family History of Vascular Disease: Specific Effects on Arterial Sites Have Implications for Genetic Studies Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 302 - 306. [Abstract] [Full Text] [PDF]
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C. S. Fox, J. F. Polak, I. Chazaro, A. Cupples, P. A. Wolf, R. A. D'Agostino, and C. J. O'Donnell Genetic and Environmental Contributions to Atherosclerosis Phenotypes in Men and Women: Heritability of Carotid Intima-Media Thickness in the Framingham Heart Study Stroke, February 1, 2003; 34(2): 397 - 401. [Abstract] [Full Text] [PDF]
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T. Mannami, T. Katsuya, S. Baba, N. Inamoto, K. Ishikawa, J. Higaki, T. Ogihara, and J. Ogata Low Potentiality of Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism as a Useful Predictive Marker for Carotid Atherogenesis in a Large General Population of a Japanese City : The Suita Study Stroke, June 1, 2001; 32(6): 1250 - 1256. [Abstract] [Full Text] [PDF]
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