(Circulation. 1997;95:2358-2367.)
© 1997 American Heart Association, Inc.
Articles |
ACE Gene Polymorphism: Ischemic Heart Disease and Longevity in 10 150 Individuals
A Case-Referent and Retrospective Cohort Study Based on the Copenhagen City Heart Study
the Department of Clinical Biochemistry (B.A.-L., B.G.N., A.T.-H.), Herlev University Hospital; the Copenhagen City Heart Study (B.G.N., G.J., A.T.-H.), Department of Medicine B (R.S.), Division of Cardiology, and Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, National University Hospital; and Danish Epidemiology Science Centre at the Institute of Preventive Medicine (T.I.A.S.), University of Copenhagen, Denmark.
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Abstract |
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Background Homozygosity for the deletion allele (D) of the angiotensin-converting enzyme (ACE) gene insertion-deletion polymorphism has been suggested to be a potent risk factor for myocardial infarction. With one exception, the samples studied so far have been small and/or ethnically heterogeneous, and most investigators have studied men only.
Methods and Results We investigated the association between ACE genotype and myocardial infarction as well as other manifestations of ischemic heart disease for both women and men in a case-referent study (n=10 150) as well as in a retrospective cohort study (n=7263). The cohort was from the ethnically homogeneous Danish population. Case subjects were from the same geographic area and had ischemic heart disease. Irrespective of the assumed degree of relative penetrance of the D allele, the odds ratios were not significantly different from 1.0 (P>.05) for ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction. There was also no association between ACE genotype and phenotypic variation in recognized risk factors for ischemic heart disease. Finally, the relative frequency of the D allele did not change as a function of age in subjects aged from 20 to 
80 years.
Conclusions In two large studies, a case-referent study and a retrospective cohort study in an ethnically homogeneous white population, there was no evidence for a statistically significant difference in the development of myocardial infarction or any other manifestations of ischemic heart disease between genotype classes of the ACE gene polymorphism in either women or men.
Key Words: genes • enzymes • cardiovascular diseases • myocardial infarction • risk factors
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Introduction |
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Recently, an interesting association between a common mutation (polymorphism) of the ACE gene and myocardial infarction was reported,1 suggesting an effect of a mutation in the ACE gene on development of ischemic heart disease. The ACE gene polymorphism is created by the insertion (I allele) or deletion (D allele) of a 287–base-pair (bp) DNA sequence within intron 16.2 In the previous study1 based on pooled analysis of 1343 men from Belfast and different parts of France, those individuals homozygous for the D allele had an increased risk of myocardial infarction, a finding that was even more pronounced in a low-risk subgroup (apolipoprotein B and body mass index below the median). These findings prompted us to initiate the present studies to further elucidate the role of the ACE gene polymorphism in ischemic heart disease.
Since then, several smaller case-control studies have confirmed an association with manifestations of ischemic heart disease3 4 5 6 7 8 9 10 11 or various other cardiac end points,7 12 13 14 although several studies found no association with the ACE gene polymorphism.15 16 17 18 19 20 21 22 23 24 Most notably, in a large, prospectively monitored cohort of US male physicians,25 the presence of the D allele of the ACE gene polymorphism conferred no appreciable risk of ischemic heart disease or myocardial infarction. Nevertheless, a recent meta-analysis26 including 15 studies comprising 8873 individuals found support for an association between the ACE D allele and myocardial infarction; however, that study also suggested publication bias toward positive results for the smaller studies.
We conducted two different studies including both women and men in the ethnically homogeneous Danish population: (1) a case-referent study of 947 case subjects with ischemic heart disease and, as the referent group, the Copenhagen City Heart Study, comprising a cohort of 9203 women and men aged 20 to 80 years; and (2) a retrospective study of survivors within the same cohort with and without myocardial infarction.
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Methods |
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Subjects
The Copenhagen City Heart Study
We studied individuals who participated in the third examination of this study from 1991 through 1994; this prospective cardiovascular population study includes an almost equal number of women (55%) and men stratified into 10-year age groups from 20 to
80 years old, drawn randomly from the population of the city of Copenhagen around the National University Hospital, Rigshospitalet, using the Copenhagen Central Population Register. A detailed description of the first (1976 through 1978) and second (1981 through 1983) examinations of this study has been published previously.27 The original cohort, supplemented with 500 20- to 24-year-olds at the second examination and 500 individuals in each of the age groups 20 through 24, 25 through 29, 30 through 34, 35 through 39, 40 through 44, and 45 through 49 years at the third examination, were all invited to participate in the third examination at Rigshospitalet, Copenhagen. Of the 17 180 individuals invited, 10 049 participated, 9259 gave blood, and 9203 were genotyped (Fig 1
). Fewer than 1% were nonwhites and 98.8% were Danish citizens, ie, for practical purposes were of Danish descent.
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Within the Copenhagen City Heart Study, retrospective information of the development of a first myocardial infarction was collected and verified until 1988 (Fig 1
; n=7263 individuals) by reviewing all hospital admissions and diagnoses (via The Danish National Hospital Discharge Register) and, if necessary, medical records from hospitals or general practitioners. Although the first examination in the Copenhagen City Heart Study was conducted from 1976 through 1978, a clear limitation of the retrospective part of the present study was that DNA was not collected until the third examination (1991 through 1994).
Patients With Ischemic Heart Disease
Nine hundred ninety-two consecutive patients from the greater Copenhagen area were referred for coronary angiography at the same hospital, Rigshospitalet, during the period from 1991 through 1993. Of these, 948 (26% women) had documented ischemic heart disease (1 subject was not genotyped) with characteristic symptoms plus at least one of the following criteria: severe stenosis on coronary angiography (>70% stenosis of at least one coronary vessel or >50% stenosis of the left main coronary artery; n=767), a previous myocardial infarction (n=494), or significant myocardial ischemia on a bicycle exercise test (Fig 1). Fewer than 1% were nonwhites and >98% were Danish citizens, ie, for practical purposes were of Danish descent. Two of the individuals who underwent coronary angiography (case subjects in the case-referent study) were also registered as participants with myocardial infarction in the retrospective cohort study.
Laboratory Methods
Cholesterol and triglycerides were determined enzymatically (CHOD-PAP, GPO-PAP, Boehringer Mannheim). HDL cholesterol was measured in the supernatant after precipitation of apolipoprotein B–containing lipoproteins (Boehringer Mannheim). Apolipoproteins A-I and B and lipoprotein(a) were measured by use of end-point turbidimetry with commercially available antisera (sheep anti-human apolipoprotein A-I and B, Boehringer Mannheim; rabbit anti-human lipoprotein(a), DAKO A/S).
Detection of the ACE Gene Polymorphism
Total genomic DNA was extracted from frozen whole blood as previously described.28 The insertion/deletion polymorphism of 287 bp in intron 16 of the ACE gene was identified by conventional polymerase chain reaction (PCR) using two primers flanking the site of the insertion.2 Fragments of 
190 bp (D allele) and 490 bp (I allele) were separated on a 2% agarose gel, stained with ethidium bromide, and visualized on a UV transilluminator.
Misclassification of ID Genotypes
Because the D allele in heterozygotes is amplified preferentially, probably due to its smaller size, all samples apparently homozygous for the D allele were subjected to a second PCR amplification with an insertion-specific primer.25 In agreement with the findings of others,25 4% to 5% of the individuals with the ID genotype were misclassified as DD with the insertion-spanning primers. All presented data are corrected for this misclassification.
Statistical Methods
Statistical analysis was performed by use of the SPSS program.29 30 To test for differences in various characteristics, Student's t test was used for continuous variables and Pearson's 
2 test was used for categorical variables. One-way ANOVA was used to test for differences in means of phenotypic characteristics between the three ACE genotypes. For the Student's t test and ANOVA, plasma triglycerides and plasma lipoprotein(a) were logarithmically transformed (log10) before the analysis to approach normal distribution; the criteria for transformation of a continuous variable were inspection of the distribution of that variable with and without various transformations and comparison with a normal distribution. Allele frequencies were estimated by the gene-counting method. Odds ratios comparing patients referred for coronary angiography with individuals in the Copenhagen City Heart Study cohort and individuals with and without myocardial infarction within the cohort were calculated. Pearson's 2 test was used as a test of independence. Logistic regression analysis with forced entry between the dependent variable (ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction) and the independent variables (ACE genotype, age, and cardiovascular risk factors) was performed; the main aim was to determine if genotype contributed in the prediction of the dependent variables when allowances were made for traditional cardiovascular risk factors. Regression polynomials (x, x2, x3, and x4) were used to allow for dependencies different from the linear on the logit scale between the dependent and independent variables. The likelihood ratio test was used to determine if the higher-degree polynomials were needed for a given covariate. The contribution of ACE genotype in predicting the dependent variables when all other independent variables were allowed for was expressed as an odds ratio (
ß) with 95% CIs (ß±1.96xSE). Homogeneity of the ability of conventional cardiovascular risk factors to predict ischemic heart disease among ACE genotype classes was tested for all cardiovascular risk factors combined (see "Results") as well as by introduction, one at a time, of all possible two-way interaction terms between ACE genotype and each of the conventional cardiovascular risk factors. The likelihood ratio test was used to examine the contribution of independent covariates as well as interaction terms in the logistic regression models. Correction for multiple comparisons was not performed in any of the analyses in the present study. A two-sided probability value of less than .05 was considered significant.
Ethical Approval
The present studies were approved by Danish ethical committees No. 100.2039/91 (Copenhagen and Frederiksberg committee) and No. KA 93125 (Copenhagen County committee).
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Results |
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All data are presented and statistical analyses were performed for women and men separately. For the Copenhagen City Heart Study cohort, all data presented are from the third examination in 1991 through 1994.
Characteristics of the Study Populations
The characteristics of participants in the case-referent and retrospective cohort studies are shown in Tables 1 and 2, respectively. In both studies, significant results are in agreement with recognized risk factors for ischemic heart disease.
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ACE Genotype and Phenotype
Mean values of recognized risk factors for ischemic heart disease are shown in Table 3 for women and men with the three different ACE genotypes. Notably, there was no statistical evidence (P>.05) to suggest that either systolic or diastolic blood pressure differed among individuals with the three different ACE genotypes.
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Relative Frequencies of ACE Genotypes and Alleles
For the case-referent study and the retrospective cohort study, relative genotype and allele frequencies in the overall group as well as in the low-risk group (defined as apolipoprotein B levels and body mass index below the median as estimated from the Copenhagen City Heart Study cohort, performed as by Cambien et al1 ) were determined for both women (Table 4) and men (Table 5). In the overall group in the Copenhagen City Heart Study cohort, the relative frequency of the D allele was 0.512 and 0.509 in women and men, respectively, with no significant difference between women and men (2: P=.88) or between individuals in the low-risk group versus the remaining individuals in the overall group (2: women, P=.97; men, P=.84). The relative frequencies of the DD, ID, and II genotypes were not significantly different from values predicted by Hardy-Weinberg equilibrium in the total Copenhagen City Heart Study cohort (2: women, P>.70; men, P>.80), in the retrospective cohort study among individuals with and without myocardial infarction combined (2: women, P>.30; men, P>.60), or in patients with ischemic heart disease (2: women, P>.70; men, P>.50) (not determined for any of the low-risk groups).
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ACE Genotype and Risk of Ischemic Heart Disease
Calculation of odds ratios for various manifestations of ischemic heart disease failed to demonstrate any statistically significant differences between ACE genotype classes in the case-referent study or in the retrospective cohort study (Tables 4 and 5). Whether DD was compared with ID and II combined or DD and ID combined was compared with II, the odds ratios in all cases were not significant for ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction in either study. This was true for the overall groups as well as for the low-risk groups and for women and men alike.
On multiple logistic regression analysis allowing for age, plasma cholesterol, HDL cholesterol, plasma triglycerides, apolipoprotein A-I, apolipoprotein B, lipoprotein(a), body mass index, hypertension, diabetes mellitus, and smoking habit, irrespective of the assumed degree of relative penetrance, the odds ratio for the ACE gene polymorphism was not significantly different from 1.0 for any of the dependent variables (ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction) in women or in men (Table 6). On the likelihood ratio test between models including and excluding ACE genotype, there was no statistical evidence to suggest that ACE genotype improved the ability to predict outcomes after considering the traditional predictors mentioned above in any of the 32 models shown in Table 6 (all P>.05). If we limited our comparison to case subjects and subjects in the referent group within the same age range, there was still no ability of ACE genotype to predict end points above that offered by traditional predictors (data not shown).
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Regression coefficients for ischemic heart disease for women and men in the case-referent study on logistic regression analysis are shown in Table 7 for the total group and for each ACE genotype separately. By comparing the likelihood value for the model including all individuals (4883 women or 4248 men) with the combined likelihood value for the three models including individuals with the DD, DI, and II genotypes, respectively, we tested for interaction between ACE genotype and the covariates shown in Table 7. The likelihood ratio test gave a significance level of .025<P<.01 for women (2=72.19, df=48) and .01<P<.005 for men (2=85.98, df=56). Subsequently, each of the covariates shown in Table 7 was tested individually for two-way interaction with genotype (coded as a categorical variable for which II genotype was the reference category) in the prediction of ischemic heart disease in the case-referent study. In women, there was a significant interaction of genotype and HDL cholesterol (P=.04), and in men, the following interactions were significant: genotype and HDL cholesterol (P=.04), genotype and apolipoprotein A-I (P=.0002), and genotype and triglycerides (P=.001).
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To examine these interactions further, the odds ratios for ischemic heart disease in each quartile of the covariate with interaction were plotted for each ACE genotype in Fig 2 (DD and ID were each compared with II). The interaction in women with HDL cholesterol appeared to be caused primarily by a higher risk of ischemic heart disease in women with the DD genotype in the third quartile and in women with the ID genotype in the fourth quartile. In men, the interaction with HDL cholesterol appeared to differ from that in women: in the third and fourth but not the first and second quartiles of HDL cholesterol, II genotype carried the highest risk. The interaction with apolipoprotein A-I was caused primarily by a high risk for ID genotype in the second quartile but not in the other three quartiles. For interaction with triglycerides in men, the pattern again differed: DD genotype conferred the greatest risk in the third quartile but not in the other three quartiles.
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ACE Genotype as a Function of Age
The relative frequency of the DD genotype as a function of age did not change from 20 to 80 years in the Copenhagen City Heart Study cohort or in patients aged from 40 to 80 years with ischemic heart disease in either women or men (Fig 3). There were also no significant differences in relative genotype frequencies in any age group in either sex between patients and individuals in the Copenhagen City Heart Study cohort.
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Discussion |
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On the basis of the results of the ECTIM study,31 Cambien et al1 were the first to report an association between the DD genotype of the ACE gene polymorphism and myocardial infarction. This association was found to be even more pronounced in subjects considered to be at low risk, defined as apolipoprotein B and body mass index below the median for the control group. That study inspired several other relatively small case-control studies of associations between ACE genotype and such diverse end points as myocardial infarction,3 5 11 23 ischemic heart disease,6 coronary atherosclerosis,4 9 10 21 dilated cardiomyopathy,7 22 coronary artery restenosis,24 hypertrophic cardiomyopathy,14 32 parental history of myocardial infarction,8 cardiac hypertrophy,12 13 and angiographic evidence of effort-induced angina,33 with conflicting results: some found positive associations with ACE genotype whereas others did not. Recently, however, a large prospective study of almost 3600 North American male physicians25 showed that the presence of the D allele or DD genotype conferred no risk of ischemic heart disease or myocardial infarction. Furthermore, in another, recently published study34 of 2439 subjects from the Framingham Heart Study,35 ACE genotype also showed no association with echocardiographically determined left ventricular mass, nor did it confer an increased risk of left ventricular hypertrophy. Some of the most obvious explanations for these differences are inadequate sample size for the majority of studies; differences, both within and between studies, in the criteria used to select patients and control subjects; differences in environmental and ethnic/genetic background; differences in age of the subjects studied; the relatively low informativeness of the marker system used; and perhaps publication bias toward positive associations. A recent meta-analysis26 including 15 studies comprising 3394 myocardial infarction case subjects and 5479 control subjects found support, within the limitations of the available data, for an association between the ACE D allele and myocardial infarction; however, that study also suggested publication bias toward positive results for the smaller studies.
One problem is represented by the differences in the selection of patients and control groups. For patients, this is illustrated by the variety of more or less unrelated biological/pathological cardiac end points reported to be associated with the DD genotype. The relative frequencies of the D allele and the DD genotype in the control samples varied from 0.30 to 0.61 and from 0.10 to 0.38,16 20 36 respectively. Some of these differences could be due to different frequencies even in white populations from different countries. This is illustrated by the fact that the relative frequencies of the D allele and the DD genotype in Danes (in the 9203 individuals in the Copenhagen City Heart Study cohort) are significantly lower than in both North American25 and French control groups1 but similar to relative frequencies in control groups from Northern Ireland,1 Austria,21 and Finland.17 However, large differences in relative frequencies of the D allele or DD genotype in normal white control groups within the same countries, as found in some smaller studies in the United Kingdom4 9 22 and the United States,3 14 20 could indicate major inconsistencies in the selection of control subjects or heterogeneous samples.
Another problem that has already been thoroughly discussed25 is the actual low informativeness of the ACE gene polymorphism as a marker system, a diallelic marker with high frequencies of both the D and I alleles, as opposed to highly informative markers with a large number of allelic variants and low frequency of the individual variant.
The study of 3600 North American male physicians25 is by far the largest study of the ACE gene polymorphism to date. Because it is a prospective study, it also has a considerably stronger study design than the smaller case-control studies. We believe that the results of that study25 together with the lack of association between ACE genotype and left ventricular hypertrophy34 cast serious doubt on the relevance of the ACE genotype in cardiovascular disease, although some critical points concerning the former study have been raised by the authors themselves,25 as well as by others.33 37 The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial designed to determine whether low-dose aspirin decreases cardiovascular mortality.38 In that study, there was a 44% reduction in the risk of myocardial infarction in the aspirin group, a fact that could seriously interfere with the interpretation of effects of the ACE gene polymorphism on the same end point, myocardial infarction.
The present study is able to avoid some of the critical points raised above concerning former studies. The Copenhagen City Heart Study is a prospective cardiovascular population study of 20 000 women and men who were selected in 1976 to be representative of the adult Danish general population from the Copenhagen area27 ; in the present study, we examined individuals who attended the third examination in 1991 through 1994, and therefore, the sample studied may not be truly representative of the general population because of selection bias between the first and third examinations of the Copenhagen City Heart Study. The study is age stratified, representing ages from 20 to 80 years. The focus of the study is on cardiovascular risk factors, and the cohort is ethnically homogeneous because <1% of the population is nonwhite and 98.8% are Danish citizens, ie, for practical purposes, they are of Danish descent. Patients with ischemic heart disease represent 992 consecutive patients from virtually the same geographic area with a similar ethnic background as the Copenhagen City Heart Study cohort. The patients were referred for coronary angiography at the same hospital during the same period as subjects in the third examination of the Copenhagen City Heart Study.
However, a clear limitation of the retrospective cohort study is that we only genotyped individuals who gave blood at the third examination (1991 through 1994). It might be that those at risk for coronary heart disease because of the presence of the ACE D allele had already suffered critical events and therefore were not seen at the third visit. We believe that there are two arguments why this is not very likely. First, the relative frequencies of the DD genotype and D allele of the 20- to 29-year-olds examined for the first time at the third examination (1991 through 1994) were not significantly different from relative genotype and allele frequencies of older individuals (up to 80 or more years old) examined at the third examination and also followed up prospectively. Individuals at risk for coronary heart disease because of a possible effect of the ACE D allele would not yet have suffered a critical event at the age of 20 to 29 years (unselected), whereas this would probably be the case for some of those at risk in the older age groups. Thus, if the ACE DD genotype or D allele was associated with an increased risk of coronary heart disease events that would prevent participation in the third examination, this should be seen as a decrease in relative genotype and allele frequencies in the older age group compared with the younger, as yet unselected group. However, these frequencies were almost identical (Fig 3). Second, for both women and men, the case-referent study, which was a completely different study design from the retrospective cohort study, compared individuals with ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction with the total Copenhagen City Heart Study cohort. The case-referent study also did not show any difference in relative frequency of DD genotype or D allele between patients and referent group or any effects on relative genotype and allele frequencies as a function of age in either group.
We detected four significant (P<.05) interactions between ACE genotype and conventional cardiovascular risk factors in the prediction of ischemic heart disease. At first, we considered these important because interaction with HDL cholesterol was found in both sexes and because two covariates associated with HDL cholesterol, apolipoprotein A-I and plasma triglycerides, were also found to interact with ACE genotype in men. However, when we plotted the unadjusted data (Fig 2), the interactions did not show monotonic and consistent associations but rather different, irregular patterns for the different covariates, which differed between the two sexes. Because of this, we considered these interactions most likely to be chance observations rather than plausible interactions, and we therefore chose not to incorporate such interaction terms in the analyses presented in Tables 6 and 7.
In conclusion, in the present study of 10 150 individuals, including both a case-referent and a retrospective cohort design, we were unable to identify the ACE gene polymorphism as a marker for ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction in women or in men, regardless of the degree of relative penetrance assumed and whether we looked at overall or low-risk groups. Furthermore, the relative frequencies of the DD genotype and D allele were statistically unaffected by age in both women and men in both studies, suggesting that the ACE gene polymorphism also did not influence longevity.
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Acknowledgments |
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This study was supported by The Danish Heart Foundation, The Danish Research Academy, Copenhagen County, and Chief Physician Johan Boserup's and Wife Lise Boserup's Fund. We thank Poul Westermann for technical assistance and Merete Appleyard for access to data from the Copenhagen City Heart Study database.
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Footnotes |
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Reprint requests to Dr Anne Tybjærg-Hansen, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Received November 12, 1996; accepted December 9, 1996.
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References |
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