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(Stroke. 2001;32:1250.)
© 2001 American Heart Association, Inc.
Original Contributions |
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
From the Department of Preventive Cardiology, National Cardiovascular Center (T.M., S.B., N.I., J.O.), and the Department of Geriatric Medicine, Osaka University Medical School (T.K., K.I., J.H., T.O.), Suita, Osaka, Japan.
Correspondence to Toshifumi Mannami, Department of Preventive Cardiology, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. E-mail mtoshi{at}hsp.ncvc.go.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Some previous studies, almost all western, have investigated whether there is a relationship between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and carotid atherosclerosis. The results, however, have not been consistently positive. Further, there have been few investigations based on a large, general population. Therefore, the present study aimed to clarify whether ACE gene deletion polymorphism was associated with carotid atherosclerosis in a large Japanese general population with a more homogeneous genetic background than Caucasian populations.
Methods—Subjects aged 30 to 86 years were randomly selected from Suita City, located in Osaka, the second largest urban area of Japan, and included 1894 men and 2137 women. With the aid of high-resolution ultrasonography, carotid atherosclerosis was evaluated using our atherosclerotic indexes of intimal-medial thickness (IMT), plaque number (PN), plaque score (PS), and percentage of stenosis of the carotid artery assessed using high-resolution B-mode ultrasonography. ACE gene I/D polymorphism was detected by polymerase chain reaction.
Results—There were no
significant differences among the ACE genotypes for age and
conventional cardiovascular risk factors, except for
systolic blood pressure (SBP) and the percentage of
hypertension in men. The values of IMT, PN, and PS as carotid
atherosclerotic indexes were not significantly different among
genotypes for either sex. After adjusting for age, body mass
index, smoking habit, high-density lipoprotein cholesterol,
triglycerides, presence of hypertension, presence of
diabetes mellitus, and presence of hyperlipidemia, the
estimated ORs for the presence of IMT 
1.10 mm (defined as
thickened IMT), according to ACE genotype
(DD versus
II,
DD+ID versus
II, and
DD versus
ID+II),
for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89
(0.70 to 1.28), respectively. On the other hand, the ORs for women
after the same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59
to 1.45), and 0.91 (0.59 to 1.27),
respectively.
Conclusions—Our present data suggest that ACE I/D polymorphism is not potentially a useful predictive marker for carotid atherogenesis when investigated in a large and homogeneous general Japanese population of 4031 subjects, a finding similar to that in a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study, an Australian study based on a general population using 1111 subjects.
Key Words: angiotensins • carotid arteries • genetics • Japan • ultrasonography
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Many previous studies have reported that carotid intimal-medial thickness (IMT) correlates with traditional cardiovascular risk factors.1 2 3 4 5 6 7 8 9 10 11 Also, it has been shown in some population-based10 11 12 13 14 15 and intervention16 17 18 studies that carotid IMT measured by B-mode ultrasound is a valid and reliable surrogate measure of generalized atherosclerosis, including coronary atherosclerosis. Recently, it has been reported19 that carotid IMT is a significant predictive value of prevalent and incident stroke as well as coronary heart disease. These findings are increasing the importance of ultrasound studies compared with studies in which the end point is defined only by the presence or absence of clinical disease, ie, stroke or myocardial infarction.
It is well known that atherosclerosis is a complicated disease influenced by genes and environmental factors, including diet, smoking, and high blood pressure. Certainly, ACE I/D polymorphism has been examined as a candidate gene polymorphism for an increased risk of ischemic heart disease20 21 22 23 24 25 26 or other cardiac end points23 27 28 29 in previous studies. However, most of those investigations assessed the relationship between ACE genotypes and myocardial infarction risk or increasing risk of hypertension. As a result, few investigations thus far have focused on the relationship between carotid atherosclerosis and gene polymorphism, although several studies30 31 32 33 34 35 with relatively small, and often selective, populations have examined the association between ACE I/D polymorphism and increased carotid IMT. In particular, no studies based on a large, general population have, to our knowledge, investigated this association, with the exception of one: an Australian study, the Perth Carotid Ultrasound Disease Assessment Study.36 Further, these results were heterogeneous and were not consistently positive.
The present study aimed to examine the relationship between ACE I/D polymorphism and carotid atherosclerosis, including carotid IMT, in a large and relatively genetically homogeneous general Japanese population.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subject Population
The population for our present study was based on a random sample selected from the residents of Suita, a city located in the second largest urban area in Japan (Osaka). Participants between the ages of 30 and 79 years were arbitrarily selected from the municipality population registry, stratified by sex and age groups of 10 years. The sample consisted of 12 200 men and women, although 3000 men and women were added randomly in the same way in 1996 and 1997. The basic sampling of the population started in 1989 with a cohort study base.
The subjects have visited the National Cardiovascular Center between Tuesday and Thursday every 2 years since then for regular health checkups, and approximately 2500 subjects have been participating in the health checkups every year. In addition to performing a routine blood examination that included total serum cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose levels, blood pressure, and anthropometric measurements, a physician or nurse administered questionnaires covering personal and family history of cardiovascular and other diseases and smoking and drinking habits. In addition, DNA was extracted from an extra 5 mL of blood withdrawn from those who visited the National Cardiovascular Center between May 1996 and February 1998. All subjects were Japanese, and only those who gave informed consent for genetic analysis were enrolled in the present study. The carotid ultrasonic examinations were begun in April 1994, but the examinations were not done on the days when the regular health checkups were performed between Tuesday and Thursday because the examinations were performed by a single physician. As the result, the subjects in the present study included 1894 men and 2137 women, aged 30 to 89 years, who attended regular health checkups and consecutively underwent the ultrasonic examinations and the genetic analysis.
Measurements
The subjects were classified as current smokers if
they smoked at least 1 cigarette per day, nonsmokers if they had never
smoked, and past smokers if they had stopped smoking for >1 year.
Subjects were defined as hypertensive if diastolic blood
pressure (DBP) was 90 mm Hg and/or systolic blood
pressure (SBP) was 140 mm Hg or if they were taking
antihypertensive medication. Those subjects whose serum total
cholesterol levels were 5.68 mmol/L (220 mg/dL) or
who were taking antihypercholesterolemic medication
were defined as having hypercholesterolemia.
Those subjects whose fasting blood glucose (FBG) levels were
7.00 mmol/L (126 mg/dL) or who were taking antidiabetic
medication were defined as diabetic. Subjects who had a history of
coronary heart disease or cerebrovascular disease (103 men and
67 women) were excluded from the present analysis. The
subjects’ blood was sampled after overnight fasting, which resulted in
the exclusion of 91 men and 113 women because they did not meet this
condition. In total, 194 men and 180 women among the present 4031
subjects were excluded from this analysis. Blood pressure was
measured twice in the right arm with a mercury sphygmomanometer, with
the subject in a sitting position after taking a short rest. The second
measurement was used for the analysis. Body mass index (BMI)
was calculated as weight (kilograms) divided by height (meters)
squared.
Blood samples drawn from the subjects after a fast of 12
hours were collected in EDTA-containing tubes. Total
cholesterol and triglycerides levels were
assayed enzymatically with a Toshiba TBA-80 mol/L biochemical discrete
analyzer. Glucose was assayed enzymatically, and HDL
cholesterol was measured after precipitation with heparin
and calcium ions with a Toshiba TBA-20R biochemical discrete
analyzer. The measurements of total cholesterol,
HDL cholesterol, and triglyceride levels were
all standardized in accordance with the protocol of the Centers for
Disease Control and Prevention.
Carotid Ultrasound
The details of the carotid ultrasonic examination
method have been already
published.10 The method used
in our present study was the same. We used a high-resolution B-mode
ultrasonic machine with 7.5-MHz transducers yielding an axial
resolution of 0.2 mm. The regions between 30 mm proximal from
the beginning of the dilation of the bifurcation bulb and 15 mm
distal from the flow divider of both common carotid arteries (CCAs)
were scanned. All measurements were made at the time of scanning with
the instrument’s electronic caliper and were recorded as
photocopies. The IMT was measured on a longitudinal scan of the CCAs at
a point 10 mm proximal from the beginning of the dilation of the
bulb. We defined IMT as the mean of the IMTs of the near and far CCA
walls at the point of measurement, and defined a mean IMT 1.10
mm as thickened IMT. We defined a plaque, a focal IMT thickening, as an
area where IMT was 1.10 mm and calculated the plaque number (PN)
by counting the number of plaques in the bilateral carotid arteries in
the scanning area. We also calculated the plaque score (PS) by totaling
the maximum thickness of all the plaques in the same area. Finally, we
defined stenosis as a condition in which a plaque occupied more
than half of the luminal circumference of an artery on a
cross-sectional scan, and the degree of stenosis was calculated
as a percentage ratio of the area of the plaque to that of the lumen,
with the following formula: (Lumen Area-Residual Lumen)/Lumen
Areax100. Both areas were measured automatically by the system on a
frozen transverse section at the maximal narrowing site. If there was
50% stenosis, another skilled ultrasonographer performed
color flow Doppler examination to confirm the
stenosis.
The intrareader reproducibility of the measurements was
assessed for the IMT of the CCA and the PN in 50 subjects just before
the start of the ultrasonic examination in the routine health checkups
in April 1994, and that matter has been described in the
publication.10 IMT and PN
were examined twice at a 1-month interval in a blinded manner for the
correlation coefficient between the first and second measurements of
IMT (r=0.87,
P<0.001). A paired
t test showed no statistically
significant difference between the 2 measurements. As for PN, 74% of
the first PN coincided with the second (
=0.68). Further, the
intrareader reproducibility of the measurement for the PS in those same
50 subjects was assessed in the present analysis using the
data of PS collected at that time. The first measurement of PS
significantly correlated with the second
(r=0.71,
P<0.01). A paired
t test also showed no
statistically significant difference between the 2
measurements.
Determination of Genotype of ACE
I/D Polymorphism
DNA was extracted from 200 µL of buffy coat
separated from fresh blood with the use of a QIAamp Kit (QIAGEN).
Template genomic DNA (100 ng) was amplified by polymerase chain
reaction with a thermal cycle (Omni Gene; Hybrid).
I/D polymorphism was
determined by agarose gel electrophoresis with ethidium bromide
staining, and the DD
genotype was reconfirmed by insertion allele–specific
amplification according to the Lindpainther’s
protocol37 with a minor
modification. This minor modification does not affect the results and
is as follows: The DNA was amplified for 30 cycles with denaturation at
94°C for 1 minute, annealing at 55°C for 30 seconds, and extension
at 72°C for 1 minute 30 seconds after initial denaturation at 94°C
for 5 minutes.
Statistical Analysis
All statistical analysis were performed
using the SAS statistical software system and
the Statistical Package for the Social Sciences (SPSS Inc). The mean
levels of all the numerical values were tested by the Student
t test. Those of almost all the
categorical values were examined by 
2
analysis. However, the Fischer exact test was adopted instead
of the 2 test in case the number of
subjects was 
5. The association between ACE
I/D polymorphism and
clinical variables, carotid atherosclerotic indices (ie, IMT, PN
and PS), was tested by 1-way ANOVA. The quantitative effects of
covariates for carotid atherosclerotic index, the presence of IMT
1.10 mm defined as thickened IMT, were assessed by multiple
logistic regression analysis with the aid of SAS. Values of
P<0.05 were considered
significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
Table 1
shows the clinical characteristics of
the present subjects by sex. Almost all variables (ie, age,
BMI, SBP, DBP, triglycerides, FBG, percentage of current
smokers, current alcohol users, diabetes, and hypertension) were
significantly higher in men than in women. The levels of total serum
cholesterol and HDL cholesterol were
significantly higher in women.
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Clinical Characteristics by Sex and ACE
I/D Polymorphism
For men, there were significant differences
(P<0.05) in SBP,
triglycerides, and the percentage of hypertension among the
3 genotypes. Also, SBP and the percentage of hypertension were
highest in the DD
genotype
(Table 2). On the other hand, for women, no significant
differences were found among the 3 genotypes with respect to
age, BMI, SBP, DBP, total serum cholesterol, HDL
cholesterol, triglycerides, FBG, the percentage
of smoking, alcohol use, diabetes, and hypertension
(Table 2).
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Genotype Distribution of ACE
I/D Polymorphism
The frequencies of the
D and I allele were 35.9%
and 64.1% for men and 35.1% and 64.9% for women. There were no
significant differences in genotype frequencies of ACE
I/D polymorphism among age
groups for either sex
(Table 3). According to Hardy-Weinberg’s expectation,
there was no significant deviation in ACE genotype distribution
for men (2=0.12,
P=0.94) for women
(2=2.23,
P=0.33), or for total subjects
(2=0.71,
P=0.70). In the present
subjects, there was no significant difference in ACE genotype
distribution (2=3.64,
P=0.16) between men and
women.
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Carotid Atherosclerotic Indexes by Sex and ACE
I/D Polymorphism
Figure 1 shows the mean IMT values of both sexes, by
ACE I/D polymorphism,
adjusted for age, pack-years of smoking, alcohol consumption, SBP,
serum total cholesterol level, HDL cholesterol,
triglycerides, and FBG. There were no significant
differences among the 3 genotypes
by 1-way ANOVA for either sex.
Figures 2 and 3 show the mean values for PN and PS,
adjusted for age, pack-years of smoking, alcohol consumption, SBP,
serum total cholesterol level, HDL cholesterol,
triglycerides, and fasting blood glucose. The results were
roughly similar to those shown in
Figure 1, and no significant differences were found among
the 3 genotypes by 1-way ANOVA.
Table 4 shows the distribution and percentage of 2
grades of stenosis (stenosis of 25% to <50% and
stenosis 50%) by sex and ACE
I/D polymorphism. There was
no significant difference among the 3 genotypes with respect to
the percentage of these 2 grades of stenosis for men. On the
other hand, for women, the percentage of these 2 grades of
stenosis of DD was
lower, though not significantly, than that of
ID and
II by Fischers exact
test.
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Distribution of the Mean IMT Divided Into 6 Classes
by Sex
The prevalence of IMT 1.10 mm, defined as
thickened IMT, was significantly
(P<0.05) higher in men than in
women (9.5% for men and 4.9% for women;
Figure 4).
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Association Between Presence of IMT 1.10
mm and ACE I/D
Polymorphism
After being adjusted for age, BMI, smoking habit,
drinking habit, HDL-C, TG, presence of hypertension, presence of
diabetes mellitus, and presence of
hypercholesterolemia, the estimated odds ratios
for the presence of IMT 1.10 mm (defined as thickened IMT),
according to ACE genotype
(DD versus
II,
DD+ID
versus II, and
DD versus
ID+II),
for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89
(0.70 to 1.28), respectively. These odds ratios for women after the
same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59 to 1.45),
and 0.91 (0.59 to 1.27), respectively
(Figure 5). In other words, there was no association
between the presence of IMT 1.10 mm (thickened IMT) and ACE
I/D polymorphism in either
sex.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Investigation of the effect of the D allele of ACE has thus far mainly focused on IHD.20 21 22 23 24 25 26 Further, a recent meta-analysis38 of 15 studies showed that there was a positive, but weak, relationship between the D allele and increased risk of myocardial infarction, although it is necessary to bear in mind that most of these results were heterogeneous and drawn from smaller, positive case-control studies. However, a large case-referent study39 using the Copenhagen City Heart Study of 10150 subjects has recently reported that there was no significant association in the development of myocardial infarction or any other manifestations of IHD. Furthermore, according to a recent review40 of meta-analyses examining the cause and effect relation between ACE I/D polymorphism and cardiovascular-renal risk among 49 959 subjects, there was no significant association of ACE I/D polymorphism with hypertension, but there was potentiality of the ACE I/D polymorphism as a useful marker of atherosclerotic cardiovascular complications and diabetic nephropathy.
However, there have been few studies30 31 32 33 34 35 36 that focused on the relationship between ACE I/D polymorphism and carotid IMT, early atherosclerotic changes, or the nearly established surrogate end point of generalized atherosclerosis. In particular, there have been few studies based on a large and homogeneous randomly sampled population, except for one, the Perth Carotid Ultrasound Disease Assessment Study.36 Even in this large study, which comprised 1111 subjects, the D allele was not found to be associated with either thickened IMT or carotid plaque formation, although some studies30 33 34 35 with small sample size or selection bias showed positive association. Also, there have been no studies showing a relationship between the D allele and carotid plaque or stenosis.
The present study, to our knowledge, is the first report
to show the lack of a relationship between ACE
I/D polymorphism and
carotid IMT based on a large, homogeneous, randomly
selected general population. Also, our present data showed that the
D allele was not associated
with the presence of IMT 1.10 mm (thickened IMT), irrespective
of whether it was considered a dominant, codominant, or recessive gene
polymorphism in either sex. Some
studies41 42 43 44 45
found an association between asymptomatic extracranial
carotid lesions and asymptomatic brain infarction, which is
thought to be a risk factor for symptomatic brain
infarction. From this evidence, there is little possibility that ACE
I/D polymorphism is a risk
factor for ischemic stroke in Japan, although a previous
Japanese study46 with
relatively small sample size (228 hypertensive and 104 normotensive
individuals) showed that there was a close relationship between the ACE
D allele and
ischemic stroke in Japanese hypertensives and that the
D allele may be an
independent risk factor for the development of cerebrovascular disease
in hypertensive patients.
It is also well known that the frequency of gene polymorphism is different among races. With regard to ACE I/D polymorphism, the D allele frequency among the present Japanese subjects was significantly lower than that in the Caucasian individuals of the Copenhagen City Heart Study39 or the Perth Carotid Ultrasound Disease Assessment Study.36 The advantages of the present study are that the participants were randomly selected from urban Japanese residents, which resulted in an all-Japanese, homogeneous population. Our previous studies10 11 (the Suita Study) have already shown that there was strong relationship between carotid IMT and various cardiovascular risk factors such as hypertension, smoking, and hypercholesterolemia. Thus, our previous and present data strongly suggest that the impact of exposure from traditional cardiovascular risk factors (such as age, hypertension, smoking, and hyperlipidemia) on carotid atherogenesis may be so much greater than that of gene polymorphisms, especially the ACE I/D polymorphism. However, the combination of some gene polymorphisms may be a risk factor for carotid atherogenesis, although this possibility should be further investigated.
In conclusion, our present data, based on a large, homogeneous general population of 4031 subjects, showed that there was little genetic influence of ACE I/D polymorphism on carotid atherogenesis and suggested that ACE I/D polymorphism might not be a potentially useful predictive marker for increased risk of carotid atherosclerosis of the Japanese. These results are similar to those of a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study,36 an Australian study based on a large general population of 1111 subjects.
Received July 29, 2000; revision received January 18, 2001; accepted February 7, 2001.
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