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Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:484-492

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:484.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

ACE Gene Polymorphism in Cardiovascular Disease

Meta-Analyses of Small and Large Studies in Whites

Birgit Agerholm-Larsen; Børge G. Nordestgaard; Anne Tybjærg-Hansen

From the Department of Clinical Biochemistry (B.A-L., A.T-H.), Herlev University Hospital, and the Department of Clinical Biochemistry (B.G.N.), Glostrup University Hospital, University of Copenhagen, Denmark.

Correspondence to Birgit Agerholm-Larsen, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail balarsen{at}image.dk


*    Abstract
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 *Abstract
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Abstract—The objective of this study was to assess the influence of the ACE gene insertion (I)/deletion (D) polymorphism on plasma ACE activity; blood pressure; and risk of myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease by comparing small and large studies. The meta-analyses are based on a literature search of MEDLINE up until April 1998 and assessment of bibliographies of published studies and reviews. Forty-six studies were selected, including a total of 32 715 white individuals. Plasma ACE activity was increased 40% and 71% for ID and DD versus II in small studies and 21% and 48% in large studies (small versus large: P<0.001 and P<0.001). Blood pressure was not influenced by genotype. Risk of myocardial infarction and ischemic heart disease was increased by 47% and 29%, respectively, for DD versus ID and II genotypes in small studies but not in large studies (small versus large: P<0.001 for risk of myocardial infarction and P=0.01 for risk of ischemic heart disease). Risk of ischemic cerebrovascular disease was not increased either in the small or in the largest study. In conclusion, the ACE gene polymorphism affects plasma ACE activity but not blood pressure and is not associated with increased risk of myocardial infarction, ischemic heart disease, or ischemic cerebrovascular disease in the largest studies.


Key Words: ACE gene insertion • deletion polymorphism • ACE activity • blood pressure • ischemic cardiovascular disease


*    Introduction
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 *Introduction
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In 1992, it was reported that the DD genotype of an insertion/deletion (I/D) polymorphism in the ACE gene predisposed carriers to myocardial infarction.1 This finding generated huge scientific interest, and a leading medical textbook now even mentions the ACE gene polymorphism as a potential cardiovascular risk factor.2 However, 2 very large studies have failed to confirm this association.3 4 5 Similarly, meta-analyses of small clinical intervention trials have on several occasions later been contradicted by large, randomized, controlled trials.6 7 8 9 10

We therefore performed meta-analyses of studies on the association between the ACE I/D gene polymorphism and plasma ACE activity; blood pressure; and risk of myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease on small and large studies separately. We also tested for evidence of sample-size bias.11


*    Methods
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 *Methods
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Search Strategy
Human studies on the ACE gene I/D polymorphism were identified by computerized literature search up until April 1998 (MEDLINE index terms: ACE or angiotensin-converting enzyme, deletion, and polymorphism), by assessment of bibliographies of published studies and reviews, and by scrutiny of major medical and cardiovascular journals. All data sources were restricted to the English language and published before April 1, 1998. A total of 228 publications were identified.

Exclusion Criteria
Studies were excluded if participants were nonwhite, if ACE activity and blood pressure were not measured in healthy control subjects or information on SD or SEM was not available, or if associations were not reported for each of the genotypes (II, ID, DD). Studies performed exclusively in patients with familial hypercholesterolemia, diabetes mellitus, or hypertension were also excluded. The exclusion of studies conducted in diabetics and hypertensive patients may flatten the association of the D allele with the end points analyzed. Studies were selected by 1 author (B.A.L.) and verified by another (B.G.N.). The exclusion criteria restricted the number of studies to 8 on plasma ACE activity (Table 1Down), 19 on blood pressure (Table 2Down), 19 on myocardial infarction (Table 3Down), 18 on ischemic heart disease (Table 3Down), and 6 on ischemic cerebrovascular disease (Table 4Down), in total 46 studies including 32 715 subjects.


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  		Table 1. Characteristics of Studies Included in the Meta-Analyses on Plasma ACE Activity


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  		Table 2. Characteristics of Studies Included in the Meta-Analyses on Blood Pressure


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  		Table 3. Characteristics of Studies Included in the Meta-Analyses on Myocardial Infarction and Ischemic Heart Disease


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  		Table 4. Characteristics of Studies Included in the Meta-Analyses on Ischemic Cerebrovascular Disease

Data Extraction
When data were reported separately for different geographical locations in the same study, this division of data was sustained in the meta-analyses. For 2 studies on blood pressure, data were entered separately for the 2 sexes because combined data were not available.12 13 When >1 control group was reported, control subjects for meta-analyses were chosen with the following priority: (1) subjects from a general population sample, (2) subjects without any acknowledged disease, (3) subjects without ischemic cardiovascular disease, and (4) subjects without the end point studied.

Absolute levels of plasma ACE activity ranged considerably from study to study. We therefore calculated the percent change in ID and DD subjects relative to II subjects. In most studies, blood pressure was measured with the subject at rest in the supine or sitting position, and myocardial infarction was defined as presence of >=2 of the following: characteristic chest pain, elevation of cardiac enzymes, and electrocardiographic results consistent with a myocardial infarction. Ischemic heart disease was a myocardial infarction, angina pectoris, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, severe stenosis (>50% to 75%) on coronary angiography, and/or myocardial ischemia on an exercise test. Ischemic cerebrovascular disease was sudden onset of focal neurological symptoms and/or evidence of severe atherosclerosis in carotid or cerebral arteries and/or evidence of a brain infarct. Data were extracted by 1 author (B.A.L.) and verified by another (B.G.N.).

Statistical Methods
A standard procedure was followed for each meta-analysis: (1) Studies were ordered by increasing statistical weight in the meta-analyses (fixed-effect model), and either pooled-effect size or odds ratio (Mantel-Haenszel approach) was calculated for all studies combined14 (a value of P<0.05 on z test was considered significant) (Figures 1 to 5DownDownDownDownDown); for myocardial infarction, a subgroup meta-analysis of subjects considered at low risk,1 ie, body mass index and apolipoprotein B below the median, was also performed. (2) The meta-analyses were tested for evidence of heterogeneity between studies (a value of P<0.05 on {chi}2 test was considered significant). (3) Funnel plots were visually examined for evidence of sample-size bias (funnel plots similar to those shown in Figures 1 through 5DownDownDownDownDown), and a statistical test for sample-size bias (funnel plot asymmetry) was performed11 (a value of P<0.1 was considered significant). (4) Meta-analyses on the smallest and largest studies were performed separately. The "smallest studies" constituted the cumulation of studies by statistical weight in the meta-analysis from the studies with the least weight upward until close to 50% of the total weight. The "largest studies" were the remaining studies, those that contributed the upper 50% of the total statistical weight in the meta-analysis. (5) A standardized z statistic was used to assess whether sufficient evidence existed for agreement or disagreement between large and smaller studies in each meta-analysis (a value of P<0.05 on z test was considered significant).9 (6) Random-effects model meta-analyses were performed for all studies combined, as well as for small and large studies separately. It is debatable whether the fixed-effects model or the random-effects model is the model of choice in studies like ours6 7 8 9 10 ; we therefore chose to use both models.



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  		Figure 1. Effect size (in percentage) of plasma ACE activity in DD and ID subjects versus II subjects. ACE indicates angiotensin-converting enzyme; DD, subjects with the genotype deletion/deletion; ID, subjects with the genotype insertion/deletion; and II, subjects with the genotype insertion/insertion.



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  		Figure 2. Effect size of systolic blood pressure in DD and ID subjects versus II subjects. Abbreviations as in Figure 1Up.



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  		Figure 3. Odds ratio for myocardial infarction in DD versus ID+II subjects. Abbreviations as in Figure 1Up.



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  		Figure 4. Odds ratio for ischemic heart disease in DD versus ID+II subjects. Abbreviations as in Figure 1Up.



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  		Figure 5. Odds ratio for ischemic cerebrovascular disease in DD versus ID+II subjects. Abbreviations as in Figure 1Up.

Aggregation of data on plasma ACE activity is complicated by the fact that different methods and scales have been used in the studies of interest. By transforming the data sets onto a natural logarithmic scale, we circumvented these differences between studies, making the data available for statistical tests. Data are shown as percentages based on untransformed data, but all statistical analyses were carried out on transformed data. However, logarithmically transformed data cannot be used without modification before entering the meta-analysis, and the following equations were therefore used before the meta-analysis: (1) µ{approx}ln(X)-1/2ln[(SD2/X2)+1] to calculate the approximated mean value of plasma ACE activity, and (2) {varsigma}{approx}ln[(SD2/X2)+1]1/2 to calculate the equivalent approximated variance (these equations are derived from the expressions of means and variance in the logarithmic normal distribution).

To test the hypothesis that plasma ACE activity is associated with ACE genotype in a dose-dependent pattern (raw data indicate II subjects to have the lowest, ID subjects intermediate, and DD subjects to have the highest ACE activity), we tested whether ID subjects have plasma ACE activity precisely intermediate between the II and DD subjects. A value of P<0.05 suggests lack of a stepwise effect of genotype on plasma ACE activity, that is, the plasma ACE activity in ID subjects is not exactly midway between activity levels in DD and II subjects (there is partial dominance or recessivity depending on the sign of the departure). We used the following equation to test the hypothesis: z=[(2xeffect size(ID versus II)) +(-1xeffect size(DD versus II))]÷[SD(mean)x([1/n(DD)x(-1)2]+(1/n(ID)x22)+{1/n(II)x[-2-(-1)]2})1/2]. Effect size(ID versus II) and effect size(DD versus II) are the estimated effect sizes from the meta-analysis of ID versus II and DD versus II, respectively. SD(mean) is the mean of the 2 SDs for effect size(ID versus II) and effect size(DD versus II), respectively. n(DD), n(ID), and n(II) are the number of subjects included in the meta-analysis for each of the 3 genotypes DD, ID, and II, respectively.


*    Results
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 *Results
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Effect sizes of comparison of ID versus II subjects and DD versus II subjects were, for plasma ACE activity, +28% (95% CI, +23% to +33%; P<0.001) and +56% (+51% to +62%; P<0.001), respectively (Figure 1Up); for systolic blood pressure, +0.7 mm Hg (-0.1 to +1.5; P=0.09) and +0.5 mm Hg (-0.3 to +1.4; P=0.24), respectively (Figure 2Up); and for diastolic blood pressure, +0.3 mm Hg (-0.1 to +0.8; P=0.13) and +0.3 mm Hg (-0.2 to +0.8; P=0.25), respectively (data not shown).

Odds ratios for the comparison of DD subjects versus ID and II subjects combined were, for myocardial infarction, 1.21 (95% CI, 1.11 to 1.32; P<0.001) (Figure 3Up); for ischemic heart disease, 1.16 (1.08 to 1.25; P<0.001) (Figure 4Up); and for ischemic cerebrovascular disease, 1.18 (1.01 to 1.37; P=0.03) (Figure 5Up). The equivalent odds ratio for myocardial infarction when only low-risk subjects were considered was 1.34 (95% CI, 1.02 to 1.75; P<0.05).

Heterogeneity
There was evidence of heterogeneity between studies in the meta-analyses for plasma ACE activity (ID versus II, P<0.01 and DD versus II, P<0.001) and for risk of myocardial infarction (DD versus ID+II, P<0.001) and ischemic heart disease (DD versus ID+II, P<0.01).

Sample-Size Bias
Visual examination of studies included in the meta-analyses indicated potential sample-size bias for plasma ACE activity (Figure 1Up) and risk of myocardial infarction (Figure 3Up), ischemic heart disease (Figure 4Up), and ischemic cerebrovascular disease (Figure 5Up). Tests for sample-size bias based on funnel plot asymmetry for plasma ACE activity and risk of myocardial infarction showed positive intercepts of the regression line deviating from the origin (P=0.07 and P=0.04, respectively), indicating that small studies in these meta-analyses showed larger effects than large studies.11

Small and Large Studies
Compared with II subjects, plasma ACE activity was increased in ID subjects by +40% (+32% to +48%; P<0.001) in small studies and by +21% (+15% to +27%; P<0.001) in large studies (small versus large, P<0.001) and increased in DD subjects by +71% (+62% to +80%; P<0.001) in small studies and by +48% (+41% to +55%; P<0.001) in large studies (small versus large, P<0.001) (Figure 1Up). The data were compatible with a stepwise effect of genotype on plasma ACE activity only in large studies (z test: P=0.74; null hypothesis: stepwise relationship between the 3 genotypes). Neither in small nor in large studies was systolic or diastolic blood pressure affected by the ACE gene polymorphism (Figure 2Up, data not shown).

Risk of myocardial infarction was increased in small studies [odds ratio, 1.47 (1.30 to 1.66; P<0.001)] but not in large studies [odds ratio, 0.99 (0.88 to 1.12; P=0.91)] (Figure 3Up) (small versus large, P=0.001); the equivalent odds ratios when only low-risk subjects were considered was 2.30 (1.53 to 3.45; P<0.001) for small studies and 0.87 (0.60 to 1.27; P=0.48) for large studies (small versus large, P<0.001). Likewise, risk of ischemic heart disease was increased in small studies [odds ratio, 1.29 (1.15 to 1.43; P<0.001)], but not in large studies [odds ratio, 1.07 (0.97 to 1.17; P=0.19)] (Figure 4Up) (small versus large, P=0.01). Risk of ischemic cerebrovascular disease was increased neither in small studies [odds ratio, 1.21 (0.97 to 1.51; P=0.46)] nor in the largest study [odds ratio, 1.15 (0.93 to 1.42; P=0.21)] (Figure 5Up) (small versus large, P=0.74).

Fixed-Effects Versus Random-Effects Model
Effect sizes of ACE genotype on plasma ACE activity and blood pressure in random-effects models were similar to those shown in Figures 1Up and 2Up for fixed-effects models. Likewise, risk of myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease (Figures 3 to 5UpUpUp) remained similar when random-effects models rather than fixed-effects models were used, all studies combined as well as on small and large studies separately, except for risk of ischemic cerebrovascular disease for all studies combined, which for the random-effects model estimated the mean risk across studies to be statistically nonsignificant [1.21 (0.98 to 1.50); P=0.08].


*    Discussion
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 *Discussion
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In agreement with the present results on all studies combined, previous meta-analyses on the ACE gene polymorphism found a strong association with plasma ACE activity,15 no association with blood pressure,15 and an association with a modest increase in risk of myocardial infarction,15 16 ischemic heart disease,15 and ischemic cerebrovascular disease.15 17 However, the present sensitivity analyses suggest that small studies show a more pronounced effect on risk of myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease and on effect size of plasma ACE activity than large studies, and the small studies may even be responsible for the overall estimate of a statistically significant odds ratio for myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease. This is further supported by evidence of heterogeneity between studies in several of the meta-analyses, by visual inspection of funnel plots, and by statistically significant evidence of sample-size bias (funnel plot asymmetry) in the meta-analyses of plasma ACE activity and risk of myocardial infarction. In addition, 2 of the previous meta-analyses15 16 suggested publication bias in small studies based on visual examination of funnel plots. Overall, this suggests selective nonpublication of small, imprecise studies with negative results and therefore no real association between the ACE gene polymorphism and risk of ischemic cardiovascular disease.

The present meta-analyses differ from the previous ones15 16 17 by inclusion of recently published articles, eg, 2 of the largest studies to date4 5 ; by exclusion of abstract-derived data, studies on nonwhite populations, and studies based entirely on patients with familial hypercholesterolemia, hypertension, or diabetes mellitus and studies that did not report data on each of the 3 genotypes (II, ID, DD) separately; and most importantly, by performing sensitivity analyses on small and large studies separately.

Taken together, the total evidence suggesting a role for the ACE gene polymorphism in ischemic cardiovascular disease is weak: (1) as mentioned above, the association may not exist, and at most the risk is increased 20% for the DD genotype (all studies combined); (2) there is no dose-response effect from II to ID to DD on risk of disease, as for plasma ACE activity; (3) findings between studies are not consistent; and finally, (4) although increased plasma ACE activity was found to predict myocardial infarction in a cross-sectional study,21 the data rather seem to suggest that the modest effect on serum ACE levels in patients is most likely the consequence and not the cause of myocardial infarction. Nevertheless, we cannot exclude the possibility that potential cardiovascular effects of the ACE gene polymorphism are restricted to certain types of patients, ie, those with or without established cardiovascular disease, diabetes, or hypercholesterolemia.

The odds ratio for myocardial infarction for DD versus ID and II was higher in individuals with body mass index and apolipoprotein B below the median than in all individuals combined. In the Copenhagen City Heart Study, the odds ratio among low-risk individuals, defined as nonsmoking, normotensive, nondiabetic subjects (cases, n=81 women and men; controls, n=3266 women and men), was 1.35 (95% CI, 0.85 to 2.16; P=0.22).

In support of the present findings, meta-analyses of small clinical intervention trials showing substantial and highly significant treatment benefits have on several occasions later been contradicted by large clinical intervention trials.6 7 8 9 10 In situations like these, the results of the smaller studies most likely represent genuine observations. However, several circumstances may account for the fact that mainly small studies with positive rather than negative results come to the attention of researchers performing meta-analyses.11

In the present meta-analysis, large studies include 1 to 5 studies, and the comparison between large and small studies is therefore sensitive to the results of these few large studies, including our own,4 5 representing observations in a limited number of contexts. However, the individual results of most of both small and large studies are in agreement with the results of our studies, with the exception of results for myocardial infarction in small studies, in which there is also evidence of sample-size or publication bias. The study by Lindpaintner et al,3 together with our own studies4 5 and a few others, is responsible for the negative results observed in the large studies. This study, being prospective, has the advantage of a longitudinal analysis and therefore of avoiding possible selection by mortality; but on the other hand, the studied population (US male physicians) may not be representative of a "standard sample." Indeed, physicians may be more aware of the control of risk factors and the assumption that medical therapy, in particular aspirin or antihypertensive drugs, reduces the incidence of ischemic heart and cerebrovascular disease.

Conversely, meta-analyses of small clinical intervention trials have on many occasions accurately predicted the results of later large clinical intervention trials.6 7 8 9 10 It therefore seems important also to consider the possibility that the ACE gene polymorphism in fact truly predicts risk of ischemic cardiovascular disease in small studies but not in large studies. It could be that cases were at higher risk of disease or were less contaminated with individuals without the correct diagnosis in small studies than in large studies and that the association therefore was seen only in small studies. The fact that 2 of the largest studies included cases with symptoms of ischemic cardiovascular disease as well as verified severe atherosclerosis speaks against this possibility.4 5 Likewise, control subjects might be better selected in small than in large studies; however, this is an unlikely explanation, because 1 of the large studies was a nested case-control study within a prospective study,3 and in 2 of the other large studies, the controls were individuals from a large general population sample.4 5 It is also possible that the ACE gene polymorphism operates only in certain contexts, those present mainly in small studies, but not in US male physicians3 or Danes.4 5 Finally, asymmetry in effect size or odds ratio relative to sample size could occur by chance alone; however, this is hard to imagine in a total of 4 of 5 end points studied in the present set of meta-analyses.

Our own studies4 5 account for 33% of the total population in the analyses and most of the subjects included in the large studies. The analysis of ischemic cerebrovascular disease and blood pressure is practically limited to the comparison of our previous studies versus the remaining studies. The present study, therefore, repeats in great part our previous observations obtained in the very homogeneous population of Denmark, results that may reflect a racial difference compared with other studies and not only the difference between large and small studies. Because this meta-analysis refers to a genetic factor, this concern seems relevant. The prognostic value of a genetic marker may be different in different populations, and a negative result obtained in a selected population is valuable information that concerns this specific group of people. Because the availability of large studies of different populations is still limited, the present comparison may have the effect of generalizing a specific observation. However, we recently determined the effect of ACE genotype on serum ACE activity in 900 women and men from the Copenhagen City Heart Study58 : 50 subjects with each of the genotypes DD, ID, and II in each of the 2 sexes were drawn randomly within each of the age groups 40 to 49, 50 to 59, and 60 to 69 years. In both women and men and in all age groups, ACE genotype explained 30% to 40% of the total variation in serum ACE activity, and this effect was codominant, with DD subjects having the highest, ID subjects intermediate, and II subjects the lowest serum ACE activity (P<0.001 for all pairwise comparisons). This rules out the possibility that the lack of association between ACE genotype and risk of ischemic cardiovascular disease in the Copenhagen City Heart Study is a result of the ACE gene not being operative in Danes. Taken together, the genotype frequencies and the effect on serum ACE activity in the Copenhagen City Heart Study are similar to those found in most other white populations (Figure 1Up).58 Thus, it is reasonable that the prognostic value of this specific genetic marker should be the same in Danes as in other white populations, unless one believes that ACE genotype does not exert its effect through serum ACE activity.

A plausible mechanism for the lack of effect of the ACE gene polymorphism on cardiovascular disease could therefore be that subjects with the DD genotype, despite having increased levels of plasma ACE, do not necessarily produce increased amounts of angiotensin II. This hypothesis is supported by the facts that (1) the ACE gene polymorphism did not affect blood pressure, despite large effects on ACE activity, and (2) >=40% of angiotensin I may be converted to angiotensin II by pathways other than ACE.59 Nevertheless, because ACE inhibition is well known to reduce blood pressure, other potential ACE genotypes that reduce plasma ACE activity to levels seen in subjects treated with ACE inhibitors may influence cardiovascular disease, because plasma ACE activity in this situation may become rate limiting in the production of angiotensin II.

A limitation of the present results is that information on use of ACE inhibitors was either absent or limited in the studies included in the present analyses and thereby impossible to correct for in the meta-analyses. ACE inhibitors influence plasma ACE levels, blood pressure, and risk of ischemic cardiovascular disease. Accordingly, if the use or effect of ACE inhibitors differs according to ACE genotype, this could have influenced our results. Another limitation is that most studies on ischemic cardiovascular disease, with the exception of the US Physician’s Health Study, included only nonfatal cases.3 If the DD genotype was in fact associated with the incidence of ischemic cardiovascular disease, the results may reflect an underestimation of the importance of the DD genotype. In fact, a study of deaths from definite or possible myocardial infarction in Belfast, Ireland, found the D allele frequency to be increased (P<0.02) among the cases of fatal myocardial infarction.60 A final limitation of the present meta-analyses is that data were taken directly from published articles and not from the original data sets provided by the various authors.

In conclusion, the present meta-analyses cast doubt on the value of the ACE DD genotype as a marker for increased risk of ischemic cardiovascular disease. The DD and ID genotypes seem to be associated with a 50% and a 20% increase in plasma ACE activity, respectively.58 New studies on the ACE gene polymorphism should study the mechanism by which the ACE gene polymorphism may affect ACE activity and focus on diseases known or suspected to be influenced by elevated levels of plasma ACE activity61 62 63 64 rather than on ischemic cardiovascular disease.


*    Acknowledgments
 
This study was supported by the Danish Heart Foundation, the Danish Medical Research Council, the Danish Research Academy, Copenhagen County, and Johann and Hanne Weimann’s Fund. Jørgen Hilden is thanked for statistical support.

Received February 8, 1999; accepted July 1, 1999.


*    References
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 up arrowAbstract
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 *References
 

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