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Originally published In Press as doi:10.1194/jlr.M400148-JLR200 on October 1, 2004

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Journal of Lipid Research, Vol. 45, 2221-2226, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting

Werner Koch1,*, Julinda Mehilli*, Arne Pfeufer{dagger},§, Albert Schömig* and Adnan Kastrati*

* Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
{dagger} Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany
§ GSF-Institut für Humangenetik, Neuherberg, Germany

Published, JLR Papers in Press, October 1, 2004. DOI 10.1194/jlr.M400148-JLR200

1 To whom correspondence should be addressed. e-mail: wkoch{at}dhm.mhn.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Experimental data support a protective function of apolipoprotein E (apoE) against restenosis, the main factor limiting the long-term benefit of percutaneous coronary interventions. We investigated the possibility that the single nucleotide polymorphisms (SNPs) –219G/T, 113G/C, 334T/C, and 472C/T of the gene encoding apoE (APOE) are associated with the incidence of death and myocardial infarction or restenosis after stenting in coronary arteries. In addition, we asked whether the apoE isotype-related {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism, defined by specific allele combinations (haplotypes) of the 334T/C and 472C/T polymorphism, and other APOE haplotypes, derived from all four SNPs investigated, are associated with adverse clinical and angiographic outcomes after stenting. Our study included 1,850 consecutive patients with symptomatic coronary artery disease (CAD) who underwent stent implantation. Follow-up angiography was performed in 1,556 patients (84.1%) at 6 months after the intervention. We found that none of the APOE SNPs is associated with death and myocardial infarction or restenosis after stenting. In addition, we observed no relationship between APOE haplotypes and adverse outcomes.

In conclusion, the APOE –219G/T, 113G/C, 334T/C, and 472C/T polymorphisms, either alone or in combination, do not represent genetic markers of the risk of thrombotic and restenotic complications in patients with CAD treated with coronary stenting.

Abbreviations: apoE, apolipoprotein E; APOE, gene encoding apolipoprotein E, CAD, coronary artery disease; CI, confidence interval; SNP, single nucleotide polymorphism

Supplementary key words coronary artery disease • APOE {varepsilon} alleles • APOE haplotypes • TaqMan genotyping


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Compared with conventional balloon angioplasty, stenting has improved the outcome of patients with coronary artery disease (CAD) (1). However, restenosis remains the principal factor limiting the long-term benefit of stenting (1). Experimental data have pointed to a protective function of apolipoprotein E (apoE) against restenosis (2–4). ApoE was found to inhibit cell signaling events associated with growth factor-induced smooth muscle cell migration and proliferation and to limit neointimal hyperplasia after arterial injury (2, 3). These results correspond to the observation that deficiency of apoE was associated with increased neointima formation after endothelial denudation (3, 4).

The apoE gene (APOE) is polymorphic, and some of its allelic forms are known to differentially affect transcriptional activity or give rise to structurally and functionally distinct protein isoforms (5–8). Evidence exists to suggest that the variability of APOE has differential effects on the atheroprotective potential attributed to apoE (5, 6). The {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism of APOE is caused by two single nucleotide polymorphisms (SNPs), 334T/C and 472C/T, which are in close physical proximity and absolute linkage disequilibrium (5, 9). The 334T/C and 472C/T SNPs exclusively determine three haplotypes, known as the {varepsilon}2 (334T/472T), {varepsilon}3 (334C/472T), and {varepsilon}4 (334C/472C) alleles of APOE (5). This heterogeneity causes variation at amino acid positions 112 (cysteine or arginine) and 158 (arginine or cysteine) of apoE, resulting in three different isoforms of apoE (5). The {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism is one of the most thoroughly studied polymorphisms, especially for its effects on lipid profiles and CAD risk (5, 6). This polymorphism was found to be relevant for apoE plasma level, receptor binding affinity of apoE, plasma lipid and lipoprotein concentrations, and CAD (5, 6). In particular, the 334C allele and the {varepsilon}4 allele were observed to impose an increased risk of CAD (5, 10), and, among patients with CAD, the {varepsilon}4 allele was related to more severe and the {varepsilon}2 allele was related to less severe disease (11). The presence of the {varepsilon}4 allele has been associated with increased death rates in patients with CAD (12, 13). The cardiovascular risk attributed to the {varepsilon}4 allele may be related to, at least in part, a lower antioxidant activity of the apoE4 isoform (112Arg/158Arg) compared with that of the apoE2 isoform (112Cys/158Cys) or the apoE3 isoform (112Cys/158Arg) (14). Another SNP of APOE, –219G/T, located in the promoter of APOE, was reported to be significantly associated with APOE promoter activity, apoE plasma concentration, and CAD (7, 8, 10). In addition, the 113G/C SNP of APOE may be relevant for APOE regulation because of its location in the APOE intron-1 enhancer element that constitutes a binding site for specific nuclear protein factors (15, 16).

Together, a number of findings suggest a significant impact of apoE and genetic variants of APOE on cardiovascular risk. APOE polymorphisms may also be associated with angiographic and clinical outcomes after subcutaneous interventions in coronary arteries. Inconsistent results were obtained regarding the relationship between the {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism and restenosis after balloon angioplasty in coronary arteries (17–20). It has not been examined whether the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs, or APOE haplotypes based on the {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism, or combinations of all four SNPs are related to thrombotic and restenotic complications after coronary stenting. We addressed this issue in a study that included a relatively large and consecutive series of patients with CAD.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The study included a consecutive series of 1,850 Caucasian patients with symptomatic CAD who underwent stent implantation at Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar der Technischen Universität München. The protocols of stent placement and poststenting therapy were described in detail elsewhere (21, 22). Postprocedural pharmacologic therapy consisted of aspirin (100 mg twice daily, indefinitely) and ticlopidine (250 mg twice daily for 4 weeks). Patients who were considered at a higher risk for ischemic complications received additional therapy with the glycoprotein IIb/IIIa blocker abciximab, which was given as a bolus injection during the stent insertion procedure and as a 12 h continuous infusion thereafter. All patients were scheduled for angiographic follow-up at 6 months. Written informed consent was obtained from the patients for the intervention, follow-up angiography, and genotype determination. The study protocol was approved by the Institutional Ethics Committee, and the reported investigations were in accordance with the principles of the current version of the Declaration of Helsinki.

ApoE genotyping
Genotyping of the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs was performed with TaqMan assays, as previously described (9).

Angiographic evaluation
Lesion morphology was classified according to the modified American College of Cardiology/American Heart Association grading system in type A, B1, B2, and C; lesions of types B2 and C were considered complex lesions. Angiograms were recorded just before and immediately after the intervention and at 6 month follow-up. Matched projections of the target lesions were selected for quantitative computer-assisted off-line analysis of the angiograms with the automated edge-detection system CMS (Medis Medical Imaging Systems, Nuenen, The Netherlands). The angiographic parameters obtained were interpolated reference diameter, lesion length, diameter stenosis before and after stenting and at follow-up, diameter of the maximally inflated balloon during stent placement, and length of the stented segment. Quantitative analysis of angiograms was performed by operators not involved in the stenting procedure and unaware of the laboratory or genetic data.

Definitions and study end points
The primary end point of the study was restenosis. Two definitions of restenosis were used: the incidence of a diameter stenosis of >=50% at 6 month follow-up angiography (angiographic restenosis) and the need for target vessel revascularization (percutaneous transluminal coronary balloon angioplasty or aortocoronary bypass grafting) as a result of symptoms or signs of ischemia in the presence of angiographic restenosis at the stented site within 1 year after stent placement (clinical restenosis). A secondary end point was the combined incidence of all-cause death and nonfatal myocardial infarction at 1 year after stenting. The diagnosis of acute myocardial infarction was based on the presence of new pathological Q waves on the electrocardiogram or a value of creatine kinase or its MB isoenzyme at least three times the normal upper limit.

Statistical analysis
Determination of haplotypes and haplotype frequencies was performed with the expectation-maximization (EM) algorithm and the Markov chain-Monte Carlo algorithm, as previously described (9). Discrete variables are expressed as counts and percentages and were compared with the Chi-square test or the Fisher exact test, as appropriate. Continuous variables are expressed as means ± SD and were compared by means of the unpaired, two-sided t-test or ANOVA for more than two groups. We tested for independent association of the APOE SNP-related genotypes and haplotype-related genotypes in multivariate models (multiple logistic regressions) of restenosis that included age, gender, arterial hypertension, hypercholesterolemia, current tobacco smoking, diabetes mellitus, unstable angina pectoris, acute myocardial infarction, previous myocardial infarction, previous bypass surgery, target coronary vessel, lesion complexity, ostial lesion, chronic occlusion, restenotic lesion, multivessel disease, reference diameter, lesion length, diameter stenosis before stenting, balloon-to-vessel ratio, maximal balloon pressure, length of the stented segment, diameter stenosis after stenting, and abciximab therapy as potentially confounding factors. Adjusted odds ratios and 95% Wald confidence intervals (CIs) were calculated on the basis of the multiple logistic regression models. Analyses were performed using the S-Plus statistical package (Mathsoft, Inc., Seattle, WA). P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient characteristics
We determined the genotypes of the –219G/T, 113G/C, 334T/C, and 472C/T SNPs of APOE in 1,850 patients with CAD who underwent stenting in coronary arteries. The distributions of the genotypes were 27.1% –219GG, 48.5% –219GT, 24.3% –219TT, 41.0% 113GG, 44.9% 113GC, 14.1% 113CC, 73.7% 334TT, 24.0% 334TC, 2.3% 334CC, and 86.8% 472CC, 12.4% 472CT, 0.8% 472TT. For comparisons with the carriers of the abundant 334TT and 472CC genotypes, patients with the rare 334CC and 472TT genotypes were combined with the patients who carried the 334TC and 472CT genotypes, respectively. Patients with the 334TC and 334CC genotypes represented the carriers of the APOE {varepsilon}4 allele, and patients with the 472CT and 472TT genotypes represented the carriers of the APOE {varepsilon}2 allele. Table 1 shows baseline clinical characteristics, lesion-related variables before stenting, and procedural parameters of the patients in relation to the genotypes of the APOE SNPs. We observed no statistically significant differences between the groups, with the following exceptions: i) patients with the –219GT genotype were younger than the carriers of the –219GG or –219TT genotype (P = 0.04); ii) reference diameter increased with the number of 113G alleles (P = 0.006); iii) in patients with the 334TT genotype, hypercholesterolemia (P = 0.04), acute myocardial infarction (P = 0.03), and periprocedural treatment with abciximab (P = 0.03) were less frequent and diabetes mellitus (P = 0.04) was more frequent than among carriers of the 334C allele (334TC genotype or 334CC genotype).


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  		TABLE 1. Baseline clinical characteristics, lesion variables before stenting, and procedural parameters according to the genotypes of the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs (n = 1,850)

 
The apoE isotype-related genotypes {varepsilon}2{varepsilon}2, {varepsilon}2{varepsilon}3, {varepsilon}2{varepsilon}4, {varepsilon}3{varepsilon}3, {varepsilon}3{varepsilon}4, and {varepsilon}4{varepsilon}4 were present at 0.8, 11.2, 1.2, 61.7, 22.8, and 2.3%, respectively. Genotype-based evaluation revealed that the alleles of the four APOE SNPs were arranged in eight different haplotypes: haplotype 1 = –219G/113G/334T/472T (GGTT; 7.0%), haplotype 2 = GGTC (41.6%), haplotype 3 = TCTC (36.3%), haplotype 4 = TGTC (0.6%), haplotype 5 = GCTC (0.2%), haplotype 6 = TGCC (11.7%), haplotype 7 = GGCC (2.6%), and haplotype 8 = TCCC (<0.001%). Haplotype 1 was the only haplotype that represented the {varepsilon}2 allele (334T/472T); haplotypes 2–5 included the {varepsilon}3 allele (334T/472C); and haplotypes 6–8 contained the {varepsilon}4 allele (334C/472C). It was possible to assign a genotype, defined by a specific combination of two of the eight haplotypes, to each patient. In total, 23 different haplotype-related genotypes were present in the study population.

Clinical and angiographic outcomes
Follow-up angiography of coronary arteries was performed in 1,556 (84.1%) of the patients 6 months after stenting. The proportions of the patients who underwent 6 month angiography were not substantially different among the SNP-related genotype groups (P >= 0.60), apoE isotype-related genotypes (P >= 0.80), and other haplotype-related genotypes (P >= 0.63). Complete 1 year clinical follow-up data were available for all patients, irrespective of the presence or absence of follow-up angiography.

APOE SNP-related genotypes
The combined incidence of all-cause death and nonfatal myocardial infarction was not significantly different between patients with the –219GG, –219GT, and –219TT genotypes (P = 0.76), patients with the 113GG, 113GC, and 113CC genotypes (P = 0.78), patients with the 334TT genotype and carriers of the 334C allele ({varepsilon}4 allele carriers) (P = 0.21), or patients with the 472CC genotype and carriers of the 472T allele ({varepsilon}2 allele carriers) (P = 0.75) (Table 2). Similarly, the need for target vessel revascularization because of symptoms or signs of ischemia in the presence of angiographic restenosis at the stented site (clinical restenosis) was not substantially different among the genotype groups of the 219G/T (P = 0.17), 113G/C (P = 0.52), 334T/C (P = 0.57), and 472C/T (P = 0.22) SNPs (Table 2). Angiographic restenosis rates were not significantly different between the genotype groups of the 219G/T (P = 0.56), 113G/C (P = 0.59), 334T/C (P = 0.10), and 472C/T (P = 0.26) SNPs (Table 2). Continuous measures of angiographic restenosis, diameter stenosis and loss index (the ratio of late lumen loss and acute lumen gain) were not substantially different between the genotype groups.


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  		TABLE 2. Death or myocardial infarction, clinical restenosis, and angiographic restenosis according to the genotypes of the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs

 
In a multivariate analysis of angiographic restenosis, we assessed the possible influence of baseline clinical characteristics, lesion-related variables, and procedural parameters on the relationship between the APOE SNPs and angiographic restenosis. After adjustment for these potentially confounding factors, the multivariate analysis did not reveal a significant independent association of the –219G/T (P = 0.31), 113G/C (P = 0.45), 334T/C (P = 0.58), or 472C/T (P = 0.36) SNP with angiographic restenosis; the adjusted odds ratios were 0.79 (95% CI = 0.50–1.25), 1.18 (95% CI = 0.77–1.79), 0.91 (95% CI = 0.65–1.27), and 1.17 (95% CI = 0.83–1.64), respectively.

ApoE isotype-related genotypes and other APOE haplotype-related genotypes
We evaluated the association of the six apoE isotype-related genotypes and the seven most frequent APOE haplotype-related genotypes, derived from four SNPs, with death and nonfatal myocardial infarction at 1 year, clinical restenosis, and angiographic restenosis. Patients who carried one of the seven frequent haplotype-related genotypes represented 89.9% of the total study population and 89.5% of the individuals with 6 month follow-up angiography. Data are shown in Table 3 (apoE isotype-related genotypes) and Table 4 (other haplotype-related genotypes). The combined incidence of all-cause death and nonfatal myocardial infarction was not significantly different between the apoE isotype-related genotype groups (P = 0.63) (Table 3) or other haplotype-related genotype groups (P = 0.95) (Table 4). Clinical restenosis rates were not substantially different between the apoE isotype-related genotype groups (P = 0.56) (Table 3) or other haplotype-related genotype groups (P = 0.97) (Table 4). No significant relationship existed between the frequency of the apoE isotype-related genotypes (P = 0.34) or other haplotype-related genotypes (P = 0.85) and angiographic restenosis (Tables 3, 4, respectively). The apparently lower rate of angiographic restenosis among the carriers of the {varepsilon}4{varepsilon}4 genotype (21.1%) versus patients with the {varepsilon}2{varepsilon}2 genotype (38.5%) (Table 3) was not significant (P = 0.21). Finally, multivariate analysis revealed no significant independent association of the apoE isotype-related genotypes (P = 0.32) or other haplotype-related genotypes (P = 0.87) with angiographic restenosis.


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  		TABLE 3. Death or myocardial infarction, clinical restenosis, and angiographic restenosis according to apoE isotype-related genotypes

 

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  		TABLE 4. Death or myocardial infarction, clinical restenosis, and angiographic restenosis according to APOE haplotype-related genotypes based on four APOE SNPs

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
ApoE activities confer protection against various forms of vascular disease, including atherosclerosis and injury-induced restenosis (3, 4, 23, 24). Stent deployment elicits local inflammation and neointima formation (25, 26). ApoE is able to inhibit the proliferation of lymphocytes and vascular smooth muscle cells (2, 27) and, therefore, may interfere with the cascade of events that leads to restenosis. We asked whether APOE polymorphisms with potential impact on APOE regulation or apoE function are suitable as predictors of clinical and angiographic outcomes after coronary stenting. The results presented here strongly suggest that the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs, the {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism, and APOE haplotype-related genotypes based on the four SNPs are not associated with death or myocardial infarction and the incidence of restenosis after stenting in coronary arteries.

The distribution of the apoE isotype-related genotypes in the present study cohort is in good agreement with the distribution of the corresponding apoE phenotypes in a Tyrolean population (28), and the genotype distribution of the –219G/T and 113G/C SNPs is similar to that observed in a study group from Spain (7).

Combined evidence suggested an association of the {varepsilon}4 allele with a higher cardiovascular risk than the {varepsilon}2 or {varepsilon}3 allele (5, 6, 8, 10–13, 17, 18). With regard to the clinical and angiographic outcomes after stenting, we observed no significant difference between patients who carried the {varepsilon}4 allele and patients who did not carry the {varepsilon}4 allele. The same was true when we compared patients with the {varepsilon}2 allele and patients without the {varepsilon}2 allele.

The association of the {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism with restenosis after balloon angioplasty of coronary arteries has been observed (17, 18), but not in all studies that addressed this subject (19, 20). In the first of the positive reports (17), the {varepsilon}4 allele and {varepsilon}4{varepsilon}4 genotype were significantly more prevalent among 59 patients with restenosis than among 91 patients who did not develop restenosis (P < 0.01 and P < 0.04, respectively). Similarly, in the second study with a positive finding (18), the {varepsilon}4{varepsilon}4 genotype was present more often among 88 patients with restenosis than among 118 patients without restenosis (P < 0.05). Enrollment in these studies was restricted to patients who fulfilled several criteria, including the absence of acute myocardial infarction and previous balloon angioplasty or coronary bypass surgery (17, 18). We do not know the reason for the differences between the results we achieved in a much larger series of consecutive patients and the results reported in relatively small samples of selected patients (17, 18). The difference in population size may be an explanation, but differences in study design and baseline characteristics of the patients offer further reasons. In addition, the disparity may result from the fact that balloon angioplasty and stenting in coronary arteries provoke distinct vascular responses: restenosis after balloon angioplasty is characterized mainly by a remodeling process that results in shrinking of the artery (29); restenosis after stenting is caused primarily by neointimal hyperplasia caused by the proliferation of vascular smooth muscle cells and the accumulation of extracellular matrix (30). For this reason, the impact, if any, of the {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphism on the outcomes after balloon angioplasty and stenting may be different.

In conclusion, the present results suggest that the APOE –219G/T, 113G/C, 334T/C, and 472C/T SNPs, either alone or in combination, are not useful as indicators of adverse outcomes in patients who undergo stenting in coronary arteries.


   ACKNOWLEDGMENTS
 
The authors thank Marianne Eichinger, Korinna Grießer, Angela Ehrenhaft, and Wolfgang Latz for skillful technical assistance.

Manuscript received April 19, 2004 and in revised form August 30, 2004.


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