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Stroke. 2006;37:2917-2923
Published online before print November 9, 2006, doi: 10.1161/01.STR.0000249011.94055.00
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(Stroke. 2006;37:2917.)
© 2006 American Heart Association, Inc.

Original Contributions

New Insight Into the Association of Apolipoprotein E Genetic Variants With Carotid Plaques and Intima-Media Thickness

Stéphanie Debette, MD; Jean-Charles Lambert, PhD; Jérôme Gariépy, MD; Nathalie Fievet, MSc; Christophe Tzourio, MD, PhD; Jean-Françoise Dartigues, MD; Karen Ritchie, MD, PhD; Anne-Mary Dupuy, MSc; Annick Alpérovitch, MD; Pierre Ducimetière, PhD; Philippe Amouyel, MD, PhD Mahmoud Zureik, MD, PhD

From the Department of Neurology, University Hospital of Lille (S.D.), Lille, France; and INSERM Units 744 (M.Z., P.A., N.F., J.C.L.), 780 (P.D.), 593 (J.F.D.), 708 (C.T., A.A.), and E 0361 (K.R., A.M.D.), Center for Cardiovascular Preventive Medicine, Hôpital Broussais (J.G.), Paris, France.

Correspondence to Mahmoud Zureik, MD, PhD, INSERM U744, Institut Pasteur de Lille, 1 rue Calmette, BP 245-59019 LILLE cedex, France. E-mail mahmoud.zureik{at}pasteur-lille.fr


*    Abstract
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 *Abstract
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 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose— Carotid plaques and elevated carotid artery intima-media thickness (IMT) are major predictors of vascular morbidity and mortality. Our aim was to test their association with 2 polymorphisms of the apolipoprotein E (apoE) gene, {epsilon} and -219G/T.

Methods— The study was performed on 5856 subjects aged ≥65 years recruited from the French population for the Three-City Study. Carotid ultrasound examination included an assessment of atherosclerotic plaques in the extracranial carotid arteries and a measurement of IMT in the common carotid arteries (CCA) at a site free of plaques. The genetic association was tested using genotype and haplotype analyses.

Results— In a multivariate analysis including both polymorphisms and vascular risk factors, carotid plaques were more frequent in {epsilon}4 homozygotes (adjusted odds ratio=2.12, 95% CI=1.27 to 3.53) and less frequent in {epsilon}2 carriers (adjusted odds ratio=0.79, 95% CI=0.66 to 0.95) compared with {epsilon}3 homozygotes. Adjusting for and stratifying on lipid levels did not modify these results. CCA-IMT was higher in carriers of the {epsilon}34 genotype (mean CCA-IMT=0.744 mm versus 0.732 mm for the {epsilon}33 genotype, P=0.002), but the association disappeared after excluding subjects with carotid plaques. No association was found between the -219 polymorphism and either carotid plaques or CCA-IMT, and there was no interaction or cis-effect between -219 and {epsilon}.

Conclusions— This study, conducted on a large population cohort of French elderly, demonstrated that carotid plaques were significantly associated with the apoE {epsilon} polymorphism independently of the -219 polymorphism and vascular risk factors, in particular lipid levels.


Key Words: apolipoproteins • carotid arteries • epidemiology • genetics • plaque


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Carotid plaques and elevated common carotid artery intima-media thickness (CCA-IMT) are associated with a higher risk of ischemic stroke, coronary events, and cardiovascular mortality.1–3 The association of several candidate genes with carotid structure has already been tested. The {epsilon} polymorphism of the apolipoprotein E (apoE) gene, located in exon 4, is one of the candidates that have received the most attention.4 Results are conflicting. Several authors have shown IMT to be higher in {epsilon}4 carriers and lower in {epsilon}2 carriers6–13; others found that IMT was higher in {epsilon}2 carriers14,15 or in subjects with the {epsilon}33 genotype5; yet others failed to show any association.16–23 The definition of IMT was variable and several studies did not take into account whether there was plaque at the site of IMT measurement. Fewer authors have tested the association between carotid plaques and the {epsilon} polymorphism, also with inconsistent results. Two studies found no association,20,24 one showed a higher frequency of plaques in {epsilon}4 carriers in hypertensive patients,18 one observed a lower frequency of plaques in {epsilon}2 carriers,11 and one a lower frequency of plaques in {epsilon}2 carriers in women only and a higher frequency of plaques in {epsilon}4 carriers in men.13

The aim of the present study was to investigate in a large population sample the association of carotid plaques and CCA-IMT with the {epsilon} polymorphism, and also with another apoE polymorphism, -219G/T, located in the promoter region whose association with carotid parameters has not been tested yet.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Study Population and Design
The Three-City (3C) Study is a prospective cohort study whose design has been described elsewhere.25 Briefly 9693 noninstitutionalized persons aged 65 years and over were recruited from the electoral rolls of 3 French cities (Bordeaux, Dijon, and Montpellier) between March 1999 and March 2001. A baseline ultrasound examination of the carotid arteries was performed in 6234 subjects (it was proposed to participants under the age of 85 who were able to come to the examination centers; as a result of logistic concerns, it was not offered to persons included during the last 4 months of subject recruitment). We retained only the 6040 subjects whose native language was French to avoid stratification bias (French law did not allow the collection of more detailed information on ethnic origin and among them the 5856 subjects who had been genotyped for the apoE -219 and {epsilon} polymorphisms; 184 subjects could not be genotyped for technical reasons).

Genotyping
The genotyping of both the {epsilon} and -219G/T polymorphism was performed by real-time polymerase chain reaction using the TaqMan assay system.26 The sequences of the primers and probes nucleotides were designed as previously described.26

Ultrasound Examination
The B-mode system (Ultramark 9 High Definition Imaging) with a 5- to 10-MHz sounding was used in all three centers, and a centralized reading was performed according to a standardized protocol.27 The examination involved scanning of the common carotid arteries, the carotid bifurcations, and the origin of the internal carotid arteries. The presence of plaques was defined as previously reported,28 and IMT was defined by the distance between the lumen-intima interface and the media-adventitia interface measured at a site free of any discrete plaque along a 10-mm-long segment of the far CCA wall.

Medical History and Standard Biologic Parameters
Information about demographic background, medical history, and personal habits was collected during a face-to-face interview using a standardized questionnaire administered by trained psychologists or nurses. Smokers were defined as ever smokers versus never smokers. "History of vascular event" was defined as a history of stroke, myocardial infarction, angina pectoris, coronary surgery, or angioplasty. Hypertension was defined according to the World Health Organization criteria by either a current blood pressure-lowering therapy or a systolic blood pressure ≥160 mm Hg and/or a diastolic blood pressure ≥95 mm Hg on two separate measures performed at baseline. Body mass index (BMI) was calculated with baseline height and weight measures and transformed into a categorical variable with 4 classes (BMI <18.5, 18.5 ≤ BMI <25, 25 ≤ BMI <30, and BMI ≥30).

Centralized measurements of fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and glucose levels were performed at baseline. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula (LDL=total cholesterol–HDL–[triglycerides/5]) and was considered as missing for triglyceride values >4.5 mmol/L. For statistical analysis, a log-transformation of triglyceride levels was performed. Hypercholesterolemia was defined as a total cholesterol ≥6.20 mmol/L and/or a cholesterol-lowering therapy, and diabetes mellitus as a fasting glucose >7 mmol/L and/or an antidiabetic therapy.

Statistics
Data were analyzed with the SAS 8.02 software package (SAS Institute Inc). Hardy-Weinberg equilibrium was tested by a {chi}2 test (1 df for the -219 polymorphism and 3 df for the {epsilon} polymorphism).

Multivariate models were adjusted for the other polymorphism, vascular risk factors (age, sex, hypertension, diabetes, smoking, BMI, total cholesterol, and triglyceride levels), history of vascular event, and study center.

The -219G/T single nucleotide polymorphism (SNP) was studied with a recessive model (TT versus TG and GG genotype) and the {epsilon} polymorphism with a general model, the {epsilon}33 genotype being the reference genotype to which the other genotypes were compared (because of their low frequency, the {epsilon}22 and {epsilon}23 genotypes were merged).

The {epsilon} polymorphism is composed of two SNPs (334T/C and 472C/T) in complete linkage disequilibrium: {epsilon}2=334T-472T, {epsilon}3=334T-472C, and {epsilon}4=334C-472C. The estimation of the D' value of linkage disequilibrium between the -219, 334, and 472 SNPs as well as the haplotype analyses was performed with the THESIAS software package29,30 (www.genecanvas.org). THESIAS infers haplotype frequencies and effects using a stochastic expectation maximization algorithm. Haplotypic effects and homogeneity are tested using the likelihood ratio criterion.29 The GTC (G-{epsilon}3) haplotype, which combines the most frequent allele of each polymorphism, was used as the reference. Haplotypes with a frequency of less than 1% were excluded.


*    Results
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 *Results
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Demographic characteristics, vascular risk factors, carotid phenotypes, and distribution of the {epsilon} and -219 alleles are given in Table 1.


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  		TABLE 1. Population Characteristics

Both the {epsilon} and -219 polymorphism were in Hardy-Weinberg equilibrium in the whole population (P=0.99 and P=0.74, respectively) and in subjects without plaques (P=0.44 and P=0.91, respectively). The D' value was –1.00 (P<0.0001) for 334T/C and 472C/T, –0.99 (P<0.0001) for -219G/T and 472C/T, and +0.56 (P<0.0001) for -219G/T and 334T/C.

The association of the {epsilon} and -219 polymorphisms with lipid levels is shown in Table 2. None of the other vascular risk factors was associated with either polymorphism. All vascular risk factors were significantly associated with the carotid plaques and CCA-IMT (data not shown).


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  		TABLE 2. Association of apoE Genotypes With Lipid Levels (mean±SD)

Carotid Plaques
{epsilon} Genotype
The frequency of carotid plaques was significantly higher in {epsilon}4 homozygotes and lower in {epsilon}2 carriers compared with {epsilon}3 homozygotes (Table 3). Similar results were found after adjusting for LDL cholesterol or hypercholesterolemia instead of total cholesterol (data not shown). There was no interaction between the {epsilon} polymorphism and lipid levels (P=0.91). Stratifying on lipid levels did not modify the results (Table 4). There was no interaction between the {epsilon} polymorphism and the other vascular risk factors or the center (P=0.89 for the latter).


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  		TABLE 3. Association of apoE Genotypes With Carotid Plaques


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  		TABLE 4. Association of Genotypes With Plaques Stratified on Total Cholesterol and LDL Cholesterol Level (univariate analysis)

The percentage of patients having no plaque, one site with plaques, and two sites with plaques was 58.2%, 18.0%, and 23.8% in {epsilon}2 carriers; 51.2%, 19.4%, and 29.4% in {epsilon}33 individuals; and 38.0%, 28.2%, and 33.8% in {epsilon}44 individuals (P=0.02). There was no association of the {epsilon} polymorphism with maximum plaque thickness measured as previously reported28 (supplemental Table I, available online at http://stroke.ahajournals.org).


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  		TABLE I. Association of the {epsilon} Polymorphism With Maximum Plaque Thickness

-219 Genotype
No association was found between the -219 genotype and carotid plaques (Table 3).

Haplotypes
The multivariate haplotype analysis showed a significant global association of all studied apoE haplotypes with carotid plaques (P=0.005). Compared with GTC (G-{epsilon}3), TCC (T-{epsilon}4) was associated with a higher frequency (odds ratio [OR]=1.21, 95% CI=1.04 to 1.41) and GTT (G-{epsilon}2) with a lower frequency of plaques (OR=0.84, 95% CI=0.71 to 0.98) (Table 5). The effect of T-{epsilon}4 compared with G-{epsilon}3 was mainly attributable to the {epsilon}4 allele. Indeed, compared with TTC (T-{epsilon}3), TCC (T-{epsilon}4) was also significantly associated with plaques (OR=1.18, 95% CI=1.01 to 1.39), whereas compared with GCC (G-{epsilon}4), TCC (T-{epsilon}4) was not associated with plaques (OR=1.0, 95% CI=0.7 to 1.5).


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  		TABLE 5. Main Haplotype Frequencies for the -219, 334, and 472 SNPs of the apoE Gene and Estimation of the Haplotypic ORs (n = 5856)

There was no cis-effect between the -219 and {epsilon} allele (ie, no interaction between the -219 and {epsilon} allele present on the same chromosome, homogeneity P=0.93).

Common Carotid Artery Intima-Media Thickness
{epsilon} Genotype
We observed a significant association of the {epsilon} genotype with CCA-IMT (Table 4). Compared with {epsilon}33, only {epsilon}34 was significantly associated with CCA-IMT (P=0.002). There was no interaction between lipid levels and the {epsilon} polymorphism (P=0.40). After excluding the 2724 subjects with carotid plaques, the association of CCA-IMT with the {epsilon} genotype was no longer significant (P=0.19).

-219 Genotype
No association was found between the -219 genotype and CCA-IMT (Table 6).


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  		TABLE 6. Association of {epsilon} and -219 Genotypes With CCA-IMT

Haplotypes
The multivariate haplotype analysis did not show a significant global effect of all studied apoE haplotypes on CCA-IMT (P=0.15). There was no cis-effect between the -219 and {epsilon} allele (homogeneity P=0.11).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
We have shown in 5856 community subjects aged 65 years or over that the frequency of carotid plaques was significantly higher in apoE {epsilon}4 homozygotes and lower in {epsilon}2 carriers independently of the apoE -219 polymorphism and of vascular risk factors, in particular lipids. CCA-IMT was higher in {epsilon}34 carriers. We did not find any association between -219G/T and either carotid plaques or CCA-IMT.

Limitations
This study included only noninstitutionalized individuals who were able to come to the study examination centers. This may explain the differences previously reported27 in cardiovascular risk factors between participants who had ultrasound examinations and those who had not. We thus cannot completely exclude potential effects of selective survival and self-selection biases leading to an underrepresentation of persons in poor health. The distribution of the -219 and {epsilon} genotypes was similar to that described previously in white populations,31 and there was no significant deviation from the Hardy-Weinberg equilibrium. However, we cannot exclude that a small number of participants whose native language was French were of Caribbean or North-African origin. Nevertheless, when taking only subjects born in Metropolitan France (5268 subjects), the results were similar (data not shown). French law did not allow the collection of more detailed information on the ethnic origin. We did not study all polymorphisms of the apoE gene and we cannot exclude that another polymorphism may modify the associations that we observed. Assessment of the plaque phenotype had high reproducibility, as described elsewhere.27

Association Between the {epsilon} Polymorphism and Carotid Plaques
Besides the large size of our population, several arguments suggest that the significant association we have found between carotid plaques and the {epsilon} polymorphism was not attributable to chance: (1) the association remained significant when adjusting for vascular risk factors, including lipid levels; (2) the haplotype analysis showed an association between the {epsilon} allele and the presence of carotid plaques, independently of the -219 allele present on the same chromosome; and (3) there was a linear trend between the number of sites with plaques and the {epsilon} genotype. The size of the association may seem relatively modest. However, most genetic associations with multifactorial diseases have modest effect size with ORs ranging between 1.2 and 1.5, and large studies typically suggest weaker associations than smaller ones.32

Overall, our results were consistent with the only two previous studies performed on large population-based samples.11,13 The first found that plaques were less frequent in {epsilon}2 carriers11 with a trend for an association of {epsilon}44 homozygotes with the presence of more than three plaques, and the second showed that the frequency of plaques was reduced in {epsilon}2 carriers in women and increased in {epsilon}4 carriers in men13 with a significant interaction between the {epsilon} genotype and gender. There was no such interaction in our study.

Interestingly, we showed that the association between {epsilon} and carotid plaques was similar when adjusting for and stratifying on lipid levels, suggesting that mechanisms other than lipid metabolism might be involved. In addition to its key role in lipoprotein transport, apoE also modulates platelet aggregation and lymphocyte proliferation, interacts with the extracellular matrix, and protects against oxidative stress.33,34

Association Between the {epsilon} Polymorphism and Common Carotid Artery Intima-Media Thickness
Previous data on the association between IMT and the {epsilon} polymorphism are conflicting, but the population size was small in the majority of the studies and the method for measuring IMT was heterogeneous. In particular, not all studies measured the IMT at a site free of plaque. The only two large population-based studies found (1) that carriers of {epsilon}22 or {epsilon}23 had a significantly thinner IMT but the effect was considered small11 and (2) that {epsilon}44 was associated with a higher IMT, but the result was not significant in a multivariate model.13

We found that CCA-IMT was increased in {epsilon}34 carriers. The mean difference of CCA-IMT was, however, small and there was no global haplotypic effect. The association of the {epsilon} polymorphism with CCA-IMT was no longer significant after excluding patients with carotid plaques at another site, ie, with overt atherosclerosis.

Our study thus suggests that the apoE {epsilon} polymorphism is associated with carotid plaques but not, or only marginally, with CCA-IMT. Carotid plaques and CCA-IMT are quite different phenotypes, the former probably representing a later stage of atherosclerosis.35 Previous studies found that CCA-IMT was an independent predictor of carotid plaque occurrence,28,36 but elevated CCA-IMT may in some instances reflect a nonatherosclerotic thickening such as an adaptive response to altered shear stress,37 and the ultrasound technique is unable to differentiate an atherosclerotic from a nonatherosclerotic cause of arterial wall thickening. Interestingly, it has been shown that carotid plaques, but not carotid artery CCA-IMT, are associated with a parental history of premature death from coronary heart disease (CHD), which suggests that some heritable factors might be specifically involved in plaque formation but not in diffuse intima-media thickening.38

Association of -219G/T With Carotid Plaques and Common Carotid Artery Intima-Media Thickness
Our study is the first to test the association between -219G/Tand carotid parameters. The -219T allele was shown to be associated with myocardial infarction and the severity of CHD in two independent studies.39,40 The fact that we did not find any association between -219G/T and carotid structure may suggest that the association between -219T and CHD, if it does exist, is not explained by a higher frequency of atherosclerotic plaques.

In conclusion, in this large-scale, community-based study, we did not find any association between carotid plaques or CCA-IMT and the apoE -219 polymorphism. We found a weak association between the apoE {epsilon} polymorphism and CCA-IMT that disappeared after excluding subjects with carotid plaques. Conversely, there was a significant and consistent association between the {epsilon} polymorphism and carotid plaques with a higher frequency of plaques in {epsilon}4 homozygotes and a lower frequency in {epsilon}2 carriers, suggesting that the {epsilon} polymorphism is associated with more advanced carotid atherosclerosis. Interestingly, this association was independent of lipid levels, which warrants further studies to elucidate the underlying mechanisms.


*    Acknowledgments
 
We thank the Conseil Régional du Nord Pas-de-Calais, and we acknowledge the Génopole de Lille Nord Pas-de-Calais whose high throughput genome platform (Genoscreen) performed the genetic analysis.

Sources of Funding

The 3C Study has been conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C-Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, the Institut de Santé Publique, d’Épidémiologie et de Développement (ISPED, Bordeaux), and the Ministry of Research–INSERM Programme "Cohortes et collections de données biologiques." Biological bank was supported by an unconditional grant from Eisai Laboratories.

Disclosures

None.

Received August 2, 2006; accepted August 14, 2006.


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 up arrowAbstract
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 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
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