(Hypertension. 1996;27:1205-1209.)
© 1996 American Heart Association, Inc.
Articles |
Polymorphism of the Apolipoprotein E and Angiotensin-Converting Enzyme Genes in Japanese Subjects With Silent Myocardial Ischemia
From the Department of Geriatric Medicine, Osaka (Japan) University Medical School (Y.N., T.K., H.R., S.T., M.O., K.K., J.H., T.M., T.O.), and the Japan Research Foundation for Chronic Diseases and Rehabilitation Affiliated Hospital, Sakuragaoka Hospitel (Y.T., Y.K.), Hyogo, Japan.
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Abstract |
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Abstract The apolipoprotein
4 allele and homozygous
deletion allele (DD) of the
angiotensin-converting enzyme gene are reported to be
associated with an increase in the incidence of ischemic heart
disease. In this study, we examined whether the apolipoprotein 4
genotype and angiotensin-converting
enzyme/DD allele are associated with silent myocardial
ischemia. We screened 3920 subjects undergoing general checkups
who had no symptoms of ischemic heart disease. Seventy subjects
(2%) showed ischemic ST-segment depression during the double
two-step exercise test. One hundred and twenty control subjects
without ischemic ST-segment depression were recruited from the
same population and matched for sex, age, and blood pressure. We
performed genotyping of the apolipoprotein E gene (2, 3, and
4) and angiotensin-converting enzyme gene
(I and D) using polymerase chain
reaction–restriction fragment length polymorphism and
polymerase chain reaction, respectively. Allele frequency of 4
of the apolipoprotein E gene was higher in the ischemic group
(11%) than the nonischemic group (5%)
(
2=5.35, P<.05), but there was no
significant association between the allele or the genotype
frequency of the angiotensin-converting enzyme gene and
the incidence of ischemic ST-segment depression. Furthermore,
stepwise multiple regression analysis also revealed that total
cholesterol level and 4 genotype were predictors
of ischemic change in the exercise tolerance test
(2=12.8, P<.005,
R2=.051). These results suggest that the
apolipoprotein 4 allele is an independent genetic risk factor
for silent myocardial ischemia in Japanese subjects.
Key Words: polymorphism • genetics • apolipoprotein E • angiotensin-converting enzyme • myocardial ischemia
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Introduction |
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Ischemic heart disease is a complex disease explained by many interactions among the effects of several genetic and environmental factors. Recent advances in genetic epidemiology have revealed that some genetic variants increase the risk for IHD. Among them, a homozygous deletion allele (DD) of ACE,1 2 apo
4
polymorphism,3 and the M235T mutation of the
angiotensinogen gene4 5 have been extensively
examined as genetic risk factors for IHD. ACE/DD was also
reported to be associated with a high concentration of serum
ACE6 and LVH,7 8 9 but in some reports, it
failed to show an association with IHD5 10 ; thus, the
possibility that ACE/DD is a risk factor for IHD remains
uncertain. On the other hand, the apoE gene is located on chromosome
19, and its polymorphisms, designated 2, 3, and 4, code
for three apoE protein isoforms. The apoE locus accounts for
approximately 7% of variance in cholesterol level. The
higher LDL cholesterol levels in subjects with the apo4
allele might be related to their increased risk for
IHD.3 11 ApoE also modulates the catabolism of
triglyceride-depleted remnants of chylomicrons and
very-low-density lipoprotein via the LDL receptor and
chylomicron remnant receptor. These findings suggest that apo4
increases the risk for IHD by alterations in lipids and lipoproteins.
However, the association between asymptomatic IHD and
genetic risk factors has not been closely examined. The double two-step exercise test is the most popular test in Japan for identification of exercise-induced silent myocardial ischemia. This test seems to have lower sensitivity but higher specificity than the exercise treadmill test.12 Therefore, a significant depression of the ST segment in the double two-step exercise test indicates that the examined subject has typical silent myocardial ischemia or LVH. In this study, we examined the genetic risk for silent myocardial ischemia.
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Methods |
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Subjects and Measurements
Subjects with asymptomatic IHD were identified from visitors to Sakuragaoka Hospitel undergoing general checkups from September 1991 to March 1993 (total number, 3920; men, 3103; women, 817). Subjects who did not have any symptoms or history of IHD and were aged between 30 and 70 years were examined. We excluded subjects with atrial fibrillation, right bundle-branch block, left bundle-branch block, LVH, and old myocardial infarction detected by electrocardiography at rest. Patients with congestive heart failure (New York Heart Association functional classes II, III, and IV) including those with severe valvular disease were also excluded from the study population.
We identified 70 subjects with silent myocardial ischemia by the double two-step exercise test. The diagnostic criteria of silent myocardial ischemia were based solely on ST-segment depression.13 Horizontal or sagging ST depression of 0.05 mV or more for at least 0.08 second after the "J" point was considered positive. Junctional (low upsloping) ST-segment depression of 0.2 mV or more was also considered positive. Non–exercise-induced ischemia was defined as ST-segment depression less than the above criteria and no further electrocardiographic changes after exercise compared with at rest. One hundred and twenty control subjects with no history of IHD were recruited from this nonischemic population and were matched for sex, age, and blood pressure.
All subjects were Japanese and gave informed consent before participating in the research protocol, which was approved by the Hospital Ethics Committee. All participants completed a standard questionnaire on personal medical history, family history, smoking habits, and alcohol consumption; height, weight, and blood pressure were recorded. Blood pressure was recorded in the morning of the second day of the checkup, with subjects in the sitting position after 10 minutes of rest, and blood was drawn after a 12-hour overnight fast. Plasma total cholesterol, triglyceride (TG), HDL cholesterol, and glucose levels were measured with a standard protocol, and LDL cholesterol level was calculated by the Friedewald equation (LDL Cholesterol=Total Cholesterol-[TG/5]-HDL Cholesterol). All subjects also underwent a 75-g oral glucose tolerance test, and plasma glucose concentration was measured after 0, 60, 120, and 180 minutes.
Genotype Determination
DNA was extracted from 10 mL of whole blood with SepaGene (Sanko
Junyaku Co). PCR to detect apoE polymorphisms and the ID
polymorphism of the ACE gene was carried out with 100 ng genomic
DNA as a template. Amplification was carried out with a DNA Thermal
Cycler PJ 2000 (Perkin Elmer Co). ApoE polymorphism was determined
according to the protocol of Emi et al.14 PCR products
were digested with 1 U Hha I (Takara Shuzo Co Ltd) for 3
hours at 37°C and then electrophoresed on a 10%
polyacrylamide gel. We followed the protocol of Tiret et
al15 with minor modifications of the primers and PCR
conditions for the ACE polymorphism. PCR products were
separated by 2% agarose gel electrophoresis and visualized by ethidium
bromide staining.
Statistical Analysis
For all statistical analyses, we used the computer
software application JMP (SAS Institute Inc). Summary data are
expressed as mean±SD. A 2 analysis was
performed for assessment of the genotype distribution and other
patient characteristics between the ischemic and
nonischemic groups. With use of all variables, a
stepwise multiple regression analysis (a backward elimination
procedure) was performed for identification of variables for
predicting exercise-induced myocardial ischemia. The
genotypes of the ACE gene (II=0,
ID+DD=1), the apoE gene (subjects without 4
allele=0, subjects with 4 allele=1), age, sex, body mass
index, total cholesterol, HDL cholesterol,
triglycerides, LDL cholesterol, fasting plasma
glucose, systolic pressure, and diastolic pressure
were considered independent variables. Any variable with a
partial Wald 2 of 4.0 or more was included in the
regression, and any previously entered variable with a partial Wald
2 less than 4.0 was excluded from the
analysis.
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Results |
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The characteristics of the subjects with silent myocardial ischemia (exercise-induced ischemic group) and without ischemia (nonischemic group) are summarized in Table 1
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Allele frequency of 4 of the apoE gene was higher in the
ischemic group (11%) than in the nonischemic group
(5%) (2=5.35, P<.05) (Table 2). The frequency of subjects with 4 of the apoE gene
was higher in the ischemic group (21%) than in the
nonischemic group (9%) (2=5.25,
P<.05; odds ratio, 2.75; 95% confidence interval, 1.13 to
6.73). There was no association between allele frequency or subject
frequency of 2 of the apoE gene and silent myocardial
ischemia. The relations between apoE genotype and lipid
levels were examined in the 190 subjects who had not been treated with
antihyperlipidemic drugs (Table 3).
Subjects with 4 did not differ from subjects without 4 in the
lipid profile. However, total cholesterol and LDL
cholesterol levels were significantly lower in subjects
with than without 2.
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The distribution of polymorphism of the ACE gene is shown in Table 4. The odds ratios for ischemia in ID
and DD subjects relative to II subjects were 1.43
and 2.12, respectively, but these were not significant. The frequency
of ID+DD and DD genotypes did not differ
between the ischemic and nonischemic groups.
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To identify independent risk factors that directly affect
exercise-induced ischemia, we performed stepwise multiple
regression analysis. It revealed that only total
cholesterol level (2=7.04,
P=.008) and 4 genotype (2=5.73,
P=.02) were predictors for exercise-induced myocardial
ischemia (Table 5). Low levels of LDL
cholesterol in the phenotype 2/3 subset and high
levels in the phenotype 3/3 and 3/4 subsets were observed
(data not shown). Analysis of plasma lipid levels in the
subjects (n=162) excluding those receiving
antihyperlipidemic medications showed similar
results (data not shown).
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Discussion |
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The main finding of the present study is that the apo
4
allele is an independent genetic risk factor for
exercise-induced silent myocardial ischemia. The 4
allele appears more frequently in patients with myocardial
infarction16 and coronary
atherosclerosis17 18 than in control
subjects. Recent studies revealed that the apo4 polymorphism is
associated with an increased severity of coronary artery
disease defined by angiography19 and with an
increased risk for exercise-induced silent myocardial
ischemia in healthy, elderly men.20 As far as we
know, the present study is the first report on the association of
the apo4 genotype with silent myocardial ischemia in
a middle-aged population (mean age, 56±9 years old). Silent
ischemia is known to increase cardiac morbidity and
mortality.21 22 23 Therefore, identification of a marker for
silent ischemia should have high clinical relevance.
A number of studies have suggested that apoE polymorphism
influences atherogenesis indirectly by an effect on circulating levels
of LDL cholesterol and apoB.16 17 18 24 25 The
apo2 allele is associated with low LDL, whereas the 4
allele is associated with high LDL. The result of the present
study on the association between 2 and LDL level is
consistent with the previous report,16 but the
frequency of the 2 allele was not different between the
exercise-induced ischemic group and the
nonischemic group in the present study. Furthermore,
although the 4 allele showed an association with risk for silent
ischemia and was identified as a predictor for myocardial
ischemia, there was no association between the 4 allele
and lipid profile. These facts suggest that apoE polymorphism is
involved in the development of atherosclerosis via not
only effects on lipid levels but also other mechanisms. Recently, it
was reported that apoE is involved in immune
reactions,26 27 tissue regeneration, and
endothelial cell proliferation.28 29
Therefore, apoE polymorphism may also be related to
atherosclerosis via a direct effect on blood vessels
during the response to local injury.
ACE gene polymorphism has been well discussed with respect to its
association with myocardial infarction and coronary
atherosclerosis.2 30 31 32 Although the
possibility of ACE/DD as a risk factor for myocardial
infarction remains uncertain,5 10 studies in the Japanese
population including our study demonstrated the association with
myocardial infarction.2 33 However, our recent
study34 showed that there was no association between the
ACE/DD genotype and effort-induced angina
defined by clinical and angiographic parameters. The
present finding of no relation between ACE polymorphism and
silent myocardial ischemia was consistent with these
studies.10 34 Furthermore, we examined whether combined
analysis of polymorphism of two genes enhances the
predictability of disease as previously reported.4 35
However, we could not perform this analysis because only one
subject had both the ACE/DD and apoE/4 genotypes
in this study population. We could not exclude the possibility of a
relationship between the ACE genotype and exercise-induced
ischemia from our results, because we excluded subjects with
LVH, which is not only a risk for myocardial infarction but is also
reported to be influenced by the ACE
genotype.7 8 9
Limitations in the selection of subjects with silent myocardial ischemia in the present study should be considered. In principle, we characterized subjects with cardiac ischemia by the double two-step test, designed originally by Master.13 This method is commonly used in Japan for general checkup because it can be performed at very low cost and is noninvasive in subjects in whom resting electrocardiography is within normal limits. This test seems to have a lower sensitivity but higher specificity than the exercise treadmill test.12 Therefore, the significant depression of the ST segment in the double two-step exercise test indicates that the examined subject has typical silent myocardial ischemia or LVH. To overcome this limitation of low sensitivity, we randomly selected 120 nonischemic control subjects from more than 3000 subjects who were screened with the double two-step test and did not fulfill the criteria for ischemic changes on electrocardiography. Another limitation of the double two-step test is overestimation of ischemia in subjects with LVH. We excluded subjects with LVH according to the criteria of electrocardiography, which is less sensitive for the detection of LVH than echocardiography. To lessen the effects of LVH, we matched blood pressure between the ischemic and nonischemic groups, because blood pressure is the greatest risk factor for LVH. Therefore, we cannot discuss whether LVH and blood pressure affected silent myocardial ischemia in this study.
In conclusion, whereas both the apo4 and ACE/DD
genotypes are reported to be genetic risk factors for
myocardial infarction, only the apo4 allele and not the ACE
genotype was an independent genetic risk factor for silent
myocardial ischemia in Japanese subjects. This discrepancy
between the two genes may be caused by the different pathogeneses of
myocardial infarction and atherosclerosis. A
prospective study in the entire screened population in the present
study will provide further information about the involvement of these
genes in the development of IHD.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to Toshio Ogihara, MD, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan.
Received September 21, 1995; first decision January 11, 1996; accepted February 13, 1996.
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