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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1250-1255

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1250-1255.)
© 1996 American Heart Association, Inc.

Articles

Apolipoprotein E Alleles and Risk of Coronary Disease

A Meta-analysis

Peter W.F. Wilson; Ernst J. Schaefer; Martin G. Larson; Jose M. Ordovas

the Framingham Heart Study, National Heart, Lung, and Blood Institute (P.W.F.W.) and Boston University (M.G.L.), Framingham, and Tufts USDA Nutrition Center, Boston (E.J.S., J.M.O.), Mass.

Correspondence to Peter W.F. Wilson, MD, Framingham Heart Study, National Heart, Lung, and Blood Institute, 5 Thurber St, Framingham, MA 01701. E-mail peter@fram.nhlbi.nih.gov.


*    Abstract
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 *Abstract
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A meta-analysis was undertaken to assess the impact of apolipoprotein E (apo E) alleles ({epsilon}2, {epsilon}3, and {epsilon}4) on coronary disease in 14 published observational studies (9 clinical coronary disease and 5 coronary angiography). In comparison with {epsilon}3, the {epsilon}4 allele was associated with greater odds for coronary heart disease, and summary estimates of the odds ratios (ORs) and (95% confidence intervals) for both sexes combined were OR=0.98 (0.85-1.14) for {epsilon}2 and OR=1.26 (1.13-1.41) for {epsilon}4. Separate analyses for men and women showed similar associations. In angiographic studies the relative odds for significant coronary artery disease among both sexes combined was OR=0.76 (0.55-1.05) for {epsilon}2 and OR=1.11 (0.88-1.40) for {epsilon}4. The overall impression is that {epsilon}4 is associated with clinical and coronary disease and that results are similar in men and women.


Key Words: apolipoprotein E • coronary heart disease • meta-analysis • molecular epidemiology


*    Introduction
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First described in the 1970s, six common isoforms of apo E typically occur in plasma. They are denoted apo E 2/2, 2/3, 3/3, 3/4, 2/4, and 4/4 and are encoded by the {epsilon}2, {epsilon}3, and {epsilon}4 alleles on human chromosome 19.1 2 The {epsilon}3 allele is the most common, and {approx}60% of North Americans are homozygous for this genetic variant. The {epsilon}2 and {epsilon}4 alleles are distinguished by single amino acid substitutions at residues 112 and 158, respectively, of the 299–amino acid chain that constitutes mature apo E. Although early interest in the apo E isoforms was focused on the description of genetic defects associated with severely abnormal lipid levels,3 4 recent literature has emphasized the effects of these mutations on the normal variation of lipid levels in the general population and the impact of these alleles on CHD.5 6 7 8

The present article provides an overview of the literature concerning apo E alleles and coronary disease in middle-aged adults. Although this review draws on one prospective study of CHD death,9 the project draws largely from case-control and cross-sectional studies that have examined the prevalence of CHD according to apo E phenotype. Because most investigators who examined the relation between apo E alleles and CHD reported apo E phenotype data for both case and control subjects, it is possible with meta-analytic techniques to make an overall estimate of the association between apo E alleles and CHD from these studies.

Specific topics to be considered include whether certain isoforms or alleles, particularly {epsilon}4, are associated with an increased prevalence of CAD; the consistency of reported results; and the degree to which sex, age, or geographic location might exert an effect. In addition to reviewing the data for clinical CHD, published information that relates apo E isoforms to arteriographic CAD is considered.


*    Methods
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Medical reports based on clinical observational studies published in English after 1978, when apo E isoforms were first described, were considered for this review. Candidate articles were located by MEDLINE and manual search methods using the key words apolipoproteins, coronary heart disease, and coronary artery disease. Plasma methods, mostly isoelectric focusing, were largely used to determine apo E phenotypes for the studies considered in this review.10 The frequency of apo E phenotypes was estimated from apo E allele data where necessary.9

Only clinical studies involving adults, typically within the 40- to 70-year age span, were considered. The Premature Development of Atherosclerosis in Youth (PDAY), a large autopsy database of aortic and coronary atherosclerosis in adults 18 to 34 years, was excluded because it was not a clinical study, postmortem information was the basis for inclusion in that investigation, and subjects were younger.11 A study of premature atherosclerosis in European subjects 18 to 26 years old was also excluded because of age and the fact that the clinical context of the study was disease in parents of the participants, not the participants themselves.12

Most investigators used a case-control design,13 14 15 16 but the Framingham and European Etude Cas Temoin Infarctus du Myocarde (ECTIM) investigations were derived from community samples,6 7 and Eichner et al17 used a nested case-control approach for participants in the Multiple Risk Factor Intervention Trial (MRFIT). In the latter project, apo E phenotyping of previously frozen plasma was used for men who developed CHD and for a group of age-matched, CHD-free control subjects.5 Although most studies focused on CHD morbidity, a prospective investigation of CHD death in Finnish men 65 to 84 years old was also included.9 The Finnish investigators performed separate analyses for eastern and southwestern samples, denoted StengardE and StengardSW, respectively, and this report was considered as two separate studies for the purpose of this meta-analysis.

Reports with a full description of selection criteria were considered, and it was also required that each study reported apo E isoform information for cases and a suitable comparison group. The coronary events included MI, angina pectoris, or death from coronary disease, but it was not possible to validate diagnostic criteria across studies. For instance, in the population-based studies, MRFIT cases included nonfatal MI and CAD death, ECTIM cases were MI survivors who met the criteria of a World Health Organization surveillance program, the Framingham Study cases were subjects with a previous MI or angina pectoris, and the Finnish study of elderly men used CHD death as the end point. Separate analyses were conducted for arteriographic studies,18 19 20 21 22 in which apo E phenotypes were determined at the time of cardiac catheterization for evaluation of chest discomfort.

Comparison groups in most investigations were of the same sex as cases, but in two Japanese reports15 16 and one other investigation,13 the sex of the control subjects was not specified and their apo E phenotype frequencies were used in comparisons for men and women. Data for rare alleles such as {epsilon}1 and {epsilon}5 (total, <1% of the worldwide population5 15 16 ) were given in some reports but excluded in this analysis.

Summary estimates for the associations between apo E alleles and CHD were calculated for men, women, and overall. Statistical methods included use of single-gene models and {chi}2 methods to estimate the effect of {epsilon}2 and {epsilon}4 alleles on the relative odds of clinical CHD and arteriographic CAD for individual studies.7 23 By this method the proportion of cases and control subjects with the {epsilon}4 allele (apo E 2/4, 3/4, or 4/4) was compared with the number of persons homozygous for {epsilon}3 (apo E 3/3). Case and control subjects were also compared for the presence of {epsilon}2 (apo E 2/4, 2/3, or 2/2) relative to {epsilon}3 homozygotes. Summary estimates of the association of apo E alleles with CHD and CAD were made with the Mantel-Haenszel modification of a fixed-effects meta-analysis model24 25 26 by combining studies within each sex and then across sexes. Similar results (not shown) were obtained with the Peto modification of a fixed-effects model.24 Tests for heterogeneity were performed with the Breslow-Day technique.27


*    Results
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The relative frequencies of apo E phenotypes among CHD cases and comparison groups appear in Tables 1 and 2DownDown for men and women, respectively. The percentage of cases with the apo E 4/4 phenotype equals or exceeds the proportion of control subjects with apo E 4/4 for all reports among men. Similarly, the apo E 3/4 phenotype is more common among cases than control subjects in almost all studies of CHD in men (Table 1Down). The tendency toward a higher proportion of apo E 4/4 and 3/4 phenotypes in cases than control subjects also occurs in women (Table 2Down). No striking differences in the frequency of apo E 2/2 or 2/3 among case and control subjects were observed for either sex.


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  		Table 1. Apo E Phenotypes and Clinical CHD in Men


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  		Table 2. Apo E Phenotypes and Clinical CHD in Women and When Sex Was Not Specified

In Table 3Down the presence of arteriographic CAD in case and control subjects is compared across five studies. In most instances the frequency of apo E 4/4 but not necessarily apo E 3/4 is greater among cases. The opposite pattern is observed for apo E 2/3, and the latter phenotype tends to be less common among cases compared with control subjects.


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  		Table 3. Apo E Phenotypes and Arteriographic CAD for Both Sexes Combined

Allele frequencies of {epsilon}2 and {epsilon}4 were calculated for each study in Tables 1 and 2UpUp, and the relative odds for CHD with respect to the {epsilon}3 allele were determined by single-gene models. These results for men, women, and both sexes combined appear in Table 4Down. Because the study of Utermann et al28 did not specify the sex of either cases or control subjects, relative odds for CHD were estimated for both sexes combined. Several investigations did not include women, and the same relative odds estimate for CHD is shown in the columns for men and for both sexes combined. Each entry represents the OR, an estimate of the relative odds for CHD associated with a specific allele compared with that for the {epsilon}3 allele. At the foot of each column is a summary odds ratio. This last estimate is weighted by the variance of the contributing studies. For instance, for {epsilon}4 the OR and (95% CI) of the estimate associated with CHD in both sexes combined is 1.26 (1.13-1.41).


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  		Table 4. Apo E Alleles and Relative Odds for CHD With Respect to Apo E 3/3

Tests for heterogeneity (9 studies of men, 4 of women, and 1 of both sexes) show for {epsilon}4: Qheterogeneity=33.6 (13 df), P=.001. The study of Utermann et al,28 in which a tendency toward cardioprotection was observed for {epsilon}4, produced a result different from that in other investigations and is responsible for more than half of the heterogeneity. Without those data the results for {epsilon}4 are as follows: OR=1.44 (1.27-1.62), Qheterogeneity=13.8 (12 df), P=.32. Similarly, a heterogeneity test for {epsilon}2 including all studies in Table 4Up yields the following: Qheterogeneity=28.1 (13 df), P=.009. No single study appeared to account for the variation in the overall {epsilon}2 estimate. The report by Eto et al15 accounted for more than one third of the heterogeneity, but removal of that study from analysis did not substantially alter the overall OR estimate, and the overall impression is that {epsilon}2 is not associated with CHD. The {epsilon}4 associations with CHD for both sexes combined are shown for each study in the FigureDown. At the bottom of the FigureDown are shown two summary estimates of the relative odds of CHD associated with {epsilon}4: the first, with the study of Utermann et al, and the second without it.



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  		Figure 1. Relative odds and (95% CIs) of this estimate for clinical CHD associated with the {epsilon}4 allele are shown for several studies, identified by author and year of publication. Two overall estimates are shown at the bottom, and the overall estimate that excluded the data of Utermann et al28 is noted with an asterisk.

Table 5Down follows the same format as that for Table 4Up, except that arteriographic CAD is considered for both sexes combined. The overall relative odds for CAD associated with {epsilon}4 is OR=1.11 (0.88-1.40). The test of heterogeneity for {epsilon}4 associated with Table 5Down yields the following: Qheterogeneity=14.5 (4 df), P=.006. The data for arteriographic CAD do not support a relation with either {epsilon}2 or {epsilon}4.


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  		Table 5. Apo E Alleles and Relative Odds for Arteriographic CAD With Respect to Apo E 3/3 for Both Sexes Combined


*    Discussion
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 *Discussion
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Summary estimates for the association of {epsilon}2 and {epsilon}4 alleles with clinical CHD are based on 9 reports (a total of 10 studies, as one Finnish report is considered to be two separate studies) that included 1971 male (Table 1Up) and 181 female (Table 2Up) cases compared with a similar number of suitable control subjects. Summary estimates indicated that the relative odds for CHD among persons with the {epsilon}2 allele were 0.98 (0.85-1.14) for both sexes combined. Similar results for {epsilon}2 were obtained when the data for each sex were analyzed separately. Because the relative odds are close to 1.00 and the (95% CI) of the estimate includes 1.00, the data suggest that the relative odds for CHD are neither higher nor lower among persons with the {epsilon}2 allele.

Information for the {epsilon}4 allele suggests an association with higher relative odds for CHD among men, women, and both sexes combined (Table 4Up and the FigureUp). The relative odds of 1.38 (1.22-1.57) for men indicate that the odds associated with the {epsilon}4 allele (apo E 2/4, 3/4, or 4/4) are 38% higher than in apo E 3/3 men. Significant heterogeneity for the estimates in Table 4Up is evidence for disparity between studies. For instance, for the association of the {epsilon}4 allele with CHD for both sexes combined, the study of Utermann et al28 suggests a decrease; the studies of Cumming and Robertson,13 Lenzen et al,14 and Yamamura et al16 show a nonsignificant increase; and the reports of Luc et al,6 Wilson et al,7 Stengard et al9 (southwestern region), Eto et al,15 and Eichner et al17 show a significant increase. Significant heterogeneity in the {epsilon}4 estimate for both sexes combined is largely attributed to the study by Utermann et al, an early report that did not identify the sex of cases or control subjects. When those data are included, however, the {epsilon}4 effect is significant; with that study removed, the {epsilon}4 effect is stronger and more significant.

Supporting data for a significant association between {epsilon}4 and CHD are found in a report of European subjects 18 to 26 years of age that compared 635 persons with a paternal history of MI and 1259 subjects without such a history. Tiret et al12 showed that the {epsilon}4 allele frequency was 1.25 times more common among subjects whose fathers had sustained an MI.

Although fewer arteriographic studies have been published, they tend to support the clinical data and complement the autopsy information from the PDAY study, in which the {epsilon}4 allele was found to be associated with a greater degree of atherosclerosis among young adults who died traumatically.11 A recent case series of middle-aged Australian men and women lacked a control group but also demonstrated that persons with greater arteriosclerosis (ie, more vessels with clinically significant stenoses) at the time of cardiac catheterization were more likely to have the {epsilon}4 allele and less likely to have {epsilon}2.29

The actual mechanism by which the {epsilon}4 allele might increase coronary artery risk has not been entirely worked out. Although apo E has been associated with dementia of the Alzheimer type and may act as a "chaperone" to promote ß-amyloid fibril formation in the brain,30 the pathobiology of coronary lesions has largely been linked to alterations in lipid metabolism.1 Transgenic mice with an apo E deficiency tend to develop high levels of lipoprotein remnants, cutaneous foam cells, and arterial lesions.31 32 On the other hand, murine strains with overexpressed apo E show increased clearance of apo B–containing particles and reduced levels of plasma cholesterol and triglycerides.33 34 Extrapolation of findings from these animal models to humans is difficult.35 Clinical studies have shown that apo E levels tend to be highest in those with the {epsilon}2 allele, intermediate in those with {epsilon}3, and lowest in those with {epsilon}4,20 36 37 but apo E concentrations among CHD cases have been reported to be higher,38 lower,39 or no different40 41 from those in control subjects. Compared with {epsilon}3, the {epsilon}4 allele is associated with increased production and decreased peripheral catabolism of LDL particles.1 The opposite tendency is observed for {epsilon}2: fewer LDL particles are produced, LDL catabolism is enhanced, and LDL cholesterol levels are typically reduced. The {epsilon}2 allele may not be entirely benign, as it has been linked to a propensity for hypertriglyceridemia in several investigations and a meta-analysis.7 This tendency toward higher triglyceride levels may help explain why persons with the {epsilon}2 allele do not typically experience protection from clinical CHD (Table 4Up) or arteriographic CAD (Table 5Up).

Estrogen status and the apo E alleles may jointly affect lipid levels. An increase in LDL cholesterol levels at menopause may be modulated by apo E status and may be more common in women with the {epsilon}4 allele.42 The ECTIM study and Finnish reports have suggested that geography may play a role.1 6 Women living in regions farther from the equator, where the prevalence of {epsilon}4 is relatively greater, a higher fat intake traditional, and population cholesterol and triglyceride levels higher, may be particularly susceptible to an apo E gene–environment interaction that promotes CHD.

The population-attributable risk for {epsilon}4 has been estimated in two population-based studies at 12% and 15%.6 7 Because these estimates depend on the prevalence of the {epsilon}4 allele in the study sample, it is not appropriate to make such estimates in case-control studies. This attributable-risk percent is interpreted as the fraction of CHD that can be attributed to the presence of the {epsilon}4 allele and suggests that this genetic marker exerts an important influence on CHD development in Western populations. The corresponding attributable-risk percent for MI associated with familial hypercholesterolemia is 5%7 and suggests that apo E markers are important clinical phenotypes in the causation of clinical atherosclerosis. The final impression is that the {epsilon}4 allele is associated with a greater relative risk for vascular disease of the heart and that these results are similar in men and women. The role of the {epsilon}2 allele in CHD is less certain. Although the {epsilon}2 allele is associated with lower LDL cholesterol concentrations, this does not necessarily imply that {epsilon}2 is cardioprotective because of its tendency to be associated with hypertriglyceridemia.


*    Selected Abbreviations and Acronyms
 
CAD = coronary artery disease
CHD = coronary heart disease
CI = confidence interval
MI = myocardial infarction
OR = odds ratio

Received February 15, 1996; accepted March 20, 1996.


*    References
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 *References
 

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