Human Molecular Genetics, 2000, Vol. 9, No. 1 57-61
© 2000 Oxford University Press
Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations—the ECTIM Study
1INSERM U508 and 2INSERM U325, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille cedex, France, 3Faculté des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse, 59006 Lille cedex, France, 4Belfast MONICA Project, Department of Epidemiology and Public Health, The Queen’s University of Belfast, Belfast BT12 6BJ, UK, 5Strasbourg MONICA Project, Laboratoire d’Epidémiologie, Faculté de Médecine, 67085 Strasbourg cedex, France, 6INSERM U518, Faculté de Médecine Toulouse-Purpan, 31073 Toulouse cedex, France, 7INSERM U258, Hôpital Paul Brousse, 16 avenue Paul Vaillant-Couturier, 94807 Villejuif cedex, France and 8INSERM SC7, 17 rue du Fer à Moulin, 75005 Paris, France
Received 17 July 1999; Revised and Accepted 17 October 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The
4 allele of the APOE gene (APOE) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer’s disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (–491AT, –427CT and –219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case–control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the –219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09–1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE 2/3/4 polymorphism. Moreover, the –219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner (P < 0.008). These data indicate that the –219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Apolipoprotein E (APOE) plays a crucial role in lipid metabolism as a ligand for various cell-surface receptors including the low density lipoprotein (LDL) receptor, the LDL-receptor related protein and the very low density lipoprotein (VLDL) receptor. In addition to the APOE3 normal isoform encoded by the APOE
3 allele, mutations occurring in the APOE gene (APOE) at codons 158 (APOE 2 allele) and 112 (APOE 4 allele) determine the existence of two other isoforms: APOE2 and -4, respectively. The APOE 2/3/4 polymorphism has been shown to have an impact on total cholesterol, LDL-cholesterol and APOE plasma levels. Individuals carrying the APOE 4 allele had increased total cholesterol, LDL-cholesterol and decreased APOE plasma levels (1,2). Hence, the genetic impact of the APOE 2/3/4 polymorphism on total plasma cholesterol variance, estimated to be >8%, is thought to be one of the most powerful genetic components in the regulation of cholesterol levels at a population level (3,4).
Given the strong impact of high total and LDL-cholesterol plasma levels on the occurrence of coronary heart diseases (CHD) and the effect of the APOE 2/3/4 polymorphism on these parameters, the APOE 2/3/4 polymorphism is suspected to modulate CHD risk. Indeed, several matched case–control studies have shown a modest but significant increased prevalence of the APOE 4 allele in CHD patients from various populations (1,5). Nevertheless, even if APOE 4 appears as a significant genetic risk factor for CHD, individuals bearing APOE 4 do not inevitably develop this disorder. This suggests that other genetic or environmental risk factors may interact with APOE 4 in determining CHD risk.
In Alzheimer’s disease (AD), the APOE 4 allele is also strongly associated with an increased risk of developing the disease but, as in CHD, individuals bearing APOE 4 do not necessarily develop dementia (6). It was lately proposed that together with the qualitative modification of the APOE structure due to the APOE 4 allele, quantitative variations of APOE mRNA expression played a major role in risk determination (7). Reinforcing this hypothesis, polymorphisms in the APOE regulatory region have been recently described at positions –491AT, –427TC and –219GT (also called Th1/E47cs), and associated with the risk of developing AD (8,9). In particular, the –219GT polymorphism was shown to have functional activity in vitro (10) and to significantly modify APOE allelic mRNA expression levels in human AD brain tissue (11).
Since the APOE locus has been implicated in the genetic predisposition to myocardial infarction (MI), we tested in a large multicentre case–control study of MI whether the –491AT, –427TC and –219GT polymorphisms, in addition to the effect of the APOE 2/3/4 polymorphism, may modify cardiovascular risk.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Allelic and genotypic distributions were in Hardy–Weinberg equilibrium for all the polymorphisms characterized (Table 1). A statistically significant difference in distribution between cases and controls was detected for the –219GT and APOE
2/3/4 polymorphisms, the APOE 4 and –219T alleles being more frequent in cases than controls (Table 1). As previously described in the ECTIM Study, the relative risk of MI, approximated by the odds ratio (OR), in men carrying the APOE 4 allele was significantly increased (OR = 1.35, 95% CI: 1.08–1.69, P < 0.008) compared with non-carriers. Furthermore, in men carrying the –219T allele, the risk of developing MI was also significantly increased (OR = 1.25, 95% CI: 1.07–1.47, P < 0.005) (Table 2). After adjustment of covariates, the increased relative risks associated with the APOE 4 allele and the –219T allele remained significant (Table 2).
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The previously described strong linkage disequilibrium for the four polymorphisms (8,9,11) was verified in the present study (Table 3). Therefore, we estimated the effect of each polymorphism on MI risk independently of the others by multivariate regression analysis (Table 2). These data indicated that the risk associated with the presence of the APOE
4 and –219T alleles was borderline significant (OR = 1.35, 95% CI: 1.02–1.78, P < 0.04 and OR = 1.23, 95% CI: 1.03–1.46, P < 0.02, respectively). In order to complete the multiple regression approach, we stratified our sample into those with or without the 4 allele (Table 2). In this case, the –219T allele was associated with a significant increased risk of MI in the 4– population (OR = 1.27, 95% CI: 1.05–1.54, P < 0.02) and with a similar trend in the 4+ population, the lack of significance being likely due to the sample size (OR = 1.23, 95% CI: 0.85–1.82, P < 0.25).
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Assuming that the presence of both the APOE
4 and –219T alleles would be a powerful risk factor for early-onset MI, we compared the estimated frequencies of the APOE 2/3/4–219GT haplotypes between cases aged 55 years or less at the date of onset and cases aged >55 years (median age of onset). The frequency of the APOE 4/–219T haplotype was significantly higher in younger than in older cases (14.0 versus 9.1%; P < 0.04). Conversely, frequencies of the other haplotypes did not statistically differ between young and old cases. Moreover, in APOE 44 homozygous cases, the mean age of the ten –219TT bearers was 49.6 ± 8.8 years whereas it was 57.8 ± 7.6 years for the eight –219TT non-bearers (non-parametric Wilcoxon test: P < 0.04).
Given the key role of APOE in circulating lipid metabolism, the major impact of plasma lipids on cardiovascular disease and the effect of the –219GT polymorphism on MI risk, we tested the impact of the –219GT polymorphism on various lipid and lipoprotein plasma concentrations in non-treated controls participating in the study. The –219GT polymorphism was not associated with significant differences in lipid and lipoprotein plasma levels. However, we identified a highly significant difference in plasma APOE concentrations according to the –219GT genotype (P < 0.0001), plasma APOE concentrations appearing to be allele dose dependent (Table 4). The two other promoter polymorphisms had no effect on APOE plasma concentrations (data not shown). Since the APOE 2/3/4 polymorphism strongly determined the APOE concentrations (1), the impact of the –219GT polymorphism on plasma APOE was reanalysed after adjustment of the APOE 2/3/4 polymorphism and the impact of the –219T allele remained significant (P < 0.008). Furthermore, when the ECTIM control group was stratified according to APOE genotypes, similar trends of the –219GT polymorphism’s effect on APOE plasma concentrations were observed in the 33, 34 and 44 subgroups (Table 4). In a similar way, the –219T allele was only associated with decreased APOE plasma concentrations in the case group, mainly due to the TT genotype (GG: 5.1 ± 1.6; GT: 5.2 ± 1.9; TT: 4.6 ± 1.6; P < 0.006). After adjustment on the 2/3/4 polymorphisms, the statistical significance remains borderline (P < 0.04).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the ECTIM Study, our data demonstrate that the –219GT polymorphism, located in the APOE promoting sequence, significantly modulates the risk of MI, independently of the APOE
2/3/4 polymorphism. Given the role of APOE in plasma lipid metabolism, and in order to determine the mechanism by which the –219GT polymorphism may modify the risk of MI, we tested the impact of the polymorphism on the various lipid and the lipoprotein plasma concentrations. Despite a strong effect of the mutation on APOE plasma concentrations, no major effect on lipids could be observed, especially for total cholesterol and atherogenic LDL subfraction. However, we were able to associate the –219T allele with lower APOE plasma concentrations, this observation being in agreement with the previously reported lower expression of APOE associated with the presence of the –219T allele in HepG2 transfected cells (10). Other mutations affecting the APOE promoter (the –491AT and –427TC polymorphisms) did not show any effect on lipid levels or the risk of MI.
A major question concerns the mechanism by which the –219GT polymorphism may influence the cardiovascular risk. Indeed, the contribution of the polymorphism to MI risk is unlikely to be mediated though a modulation of plasma lipoprotein metabolism, as has been suggested to explain the functionality of the APOE 2/3/4 polymorphism. Using HepG2 hepatoma cells as a model, Bohnet et al. (12) have demonstrated that the APOE concentrations in VLDL, in addition to the APOE 2/3/4 polymorphism, help to determine VLDL affinity for the APOE-binding receptors, and probably subsequent variations in plasma total and LDL-cholesterol levels. In the present study, plasma VLDL-cholesterol levels were highly associated with the APOE 2/3/4 polymorphism confirming that circulating VLDL-cholesterol is strongly determined by the affinity of APOE isoforms carried by VLDL lipoproteins (1). However, VLDL-cholesterol concentrations were not associated with variations at the –219GT locus, even after stratification on APOE 2/3/4 genotypes. Since the –219GT polymorphism has been shown to influence APOE expression, these data suggest that APOE concentrations in VLDL are unaffected by hepatic APOE expression. As a consequence, the –219GT polymorphism is unlikely to modulate VLDL binding affinity for the receptors, and subsequent plasma lipid and lipoprotein variations. Indeed, in our study the –219GT polymorphism was not associated with significant variation in lipid and lipoprotein plasma levels.
Since the deleterious impact of the –219T allele on MI cannot be explained by a major effect on circulating lipids, it may be mediated by more subtle and local mechanisms, involved, for instance, in the course of atherosclerotic plaque formation. Interestingly, abundant APOE, mainly produced by macrophages, is found in atherosclerotic lesions, suggesting that macrophage-derived APOE may be anti-atherogenic (13,14). Indeed, by studying the effect of macrophage-specific expression of human apoE in apoE null mice, Bellosta et al. (15) showed that this specific apoE expression reduced atherosclerotic lesion development compared with control littermates matched for cholesterol level and lipoprotein profile. Several mechanisms have been proposed to explain how macrophage-derived APOE may be anti-atherogenic, for instance: (i) ApoE may protect against oxidative stress and isoform-specific antioxidant activities have been described, the APOE2 isoform being the most effective agent and the APOE4 isoform being the lesser (16); and (ii) macrophage APOE may also modulate cholesterol balance in the arterial wall in an isoform-dependent manner (17,18), APOE2/APOE2 macro- phages secreting cholesterol more efficiently than APOE3/APOE3 or APOE4/APOE4 cells (19).
Together, these data suggest that genetically determined quantitative limitations of APOE expression may have major effects in humans, especially when they are stressed by an atherogenic diet, at least by regulating antioxidant activities and cholesterol balance within the arterial wall. In this context, the increased risk of MI and decreased APOE plasma concentrations associated with the –219T allele may suggest that, in addition to the deleterious effect of the APOE 4 allele, the basal ability of cells to synthesize and secrete APOE may be of particular relevance, irrespective, to some extent, of the isoform. With this in mind, by calculating the mean age of APOE 44 homozygotes cases according to the –219GT status, we have suggested that –219TT homozygotes may be at higher risk of MI.
In conclusion, by studying the impact of mutations affecting the APOE promoter on cardiovascular disease risk, we reinforced the probability of functionality of the –219GT polymorphism while other mutations did not seem to exert major effects. The –219GT polymorphism should significantly influence the level of synthesis of APOE which may, in addition to the specific properties of the various isoforms, be a critical determinant of physiological and pathological mechanisms involved in both cardiovascular and neuro- degenerative disorders relating to the APOE locus.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Population studied
This work was carried out in a large multicentre case–control study, the ECTIM Study (Etude Cas-Témoins de l’Infarctus du Myocarde) based on four centres participating in the WHO-MONICA Project: Lille and its suburbs, Strasbourg and the region of Bas-Rhin, Toulouse and the region of Haute-Garonne, in France, and Belfast and its surroundings in Northern Ireland (20). A total population of 587 men aged 25–64 years surviving a definite MI was recruited and compared with a random sample of 727 age-matched male controls from the same geographical areas.
Blood sampling and lipid, lipoprotein and apolipoprotein analyses
Blood sampling and lipid, apolipoprotein and lipoprotein measurements were performed according to the methods described elsewhere (20). Samples from cases were obtained between 3 and 9 months after MI.
DNA extraction and genetic analysis
Genomic DNA extraction and PCR amplifications were performed as previously described (8,9). The –491AT, –427TC, –219GT and APOE 2/3/4 genotypes could be obtained for 1245 subjects (567 cases versus 678 controls). APOE 2/3/4 was deduced from phenotyping analysis (1). For each other polymorphism, mutations were detected by adequate enzymatic digestion followed by an electrophoretic step in ethidium bromide-stained agarose or polyacrylamide gels.
Statistical analysis
The data were analysed using the SAS statistical software release 6.12 (SAS Institute, Cary, IN). Genotype frequencies were compared in cases and controls with multivariate logistic regression analysis including dummy variables to take populations and population–genotype interactions into account. Genotypes were coded according to the hypothesis tested (dose-dependent model as observed in Table 1). Extended haplotype frequencies of the four markers were estimated on collapsed data using the myriad algorithm described by McLean and Morton (21), using a computer program by Cox et al. (22). The percent of the maximum possible value of linkage disequilibrium were computed as outlined by Thompson et al. (23).
In controls, lipid and lipoprotein levels were compared between genotypes by analysis of covariance. The tests were adjusted by age, centre, body mass index, tobacco and alcohol consumption. Triglycerides and APOE plasma concentrations were analysed after log transformation. To take into account multiple adjustments, the level of significance was P < 0.01.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +33 3 20 87 77 10; Fax: +33 3 20 87 78 94; Email: philippe.amouyel@pasteur-lille.fr
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R. Peila, L.R. White, H. Petrovich, K. Masaki, G.W. Ross, R.J. Havlik, L.J. Launer, and J. Poirier Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment: The Honolulu-Asia Aging Study Editorial Comment: The Honolulu-Asia Aging Study Stroke, December 1, 2001; 32(12): 2882 - 2889. [Abstract] [Full Text] [PDF]
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 K. L. Klos, S. L. R. Kardia, R. E. Ferrell, S. T. Turner, E. Boerwinkle, and C. F. Sing Genome-Wide Linkage Analysis Reveals Evidence of Multiple Regions That Influence Variation in Plasma Lipid and Apolipoprotein Levels Associated With Risk of Coronary Heart Disease Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 971 - 978. [Abstract] [Full Text] [PDF]
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 D. A. Nickerson, S. L. Taylor, S. M. Fullerton, K. M. Weiss, A. G. Clark, J. H. Stengård, V. Salomaa, E. Boerwinkle, and C. F. Sing Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene Genome Res., October 1, 2000; 10(10): 1532 - 1545. [Abstract] [Full Text]
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