This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gerdes, L. U. Articles by Færgeman, O. Search for Related Content PubMed PubMed Citation Articles by Gerdes, L. U. Articles by Færgeman, O. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Clinical genetics Secondary prevention Acute myocardial infarction Genetics of cardiovascular disease

(Circulation. 2000;101:1366.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

The Apolipoprotein 4 Allele Determines Prognosis and the Effect on Prognosis of Simvastatin in Survivors of Myocardial Infarction

A Substudy of the Scandinavian Simvastatin Survival Study

Lars Ulrik Gerdes, MD; Christian Gerdes, MD, PhD; Kari Kervinen, MD, PhD; Markku Savolainen, MD, PhD; Ib Christian Klausen, MD; Peter Steen Hansen, MD, DMSc; Y. Antero Kesäniemi, MD, PhD; Ole Færgeman, MD, DMSc

From the Departments of Internal Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Aarhus, Denmark (L.U.G., C.G., I.C.K., P.S.H., O.F.), and the Department of Internal Medicine and Biocenter Oulu, Oulu University Hospital, Oulu, Finland (K.K., M.S., Y.A.K.).

Correspondence to Dr Lars Ulrik Gerdes, Department of Clinical Biochemistry, Aarhus Amtssygehus University Hospital, DK-8000 Aarhus C, Denmark. E-mail ulrik.gerdes{at}dadlnet.dk

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Carriers of the 4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes.

Methods and Results—Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in 4 carriers and to 0.66 (95% confidence interval, 0.35 to 1.24) in other patients (P=0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with 4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment.

Conclusions—Myocardial infarction survivors with the 4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.

Key Words: apolipoproteins • genetics • myocardial infarction • prognosis • mortality

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Molecular biology enables us to probe the relationship of countless genomic variations to a large variety of diseases. Because the number of such possible relationships is extremely large, the plausibility and clinical implications of a particular finding must be supported by statistical likelihood and by biological and epidemiological evidence.¹ The relationship is also more likely to be important if it results from pursuing an a priori hypothesis.

The common polymorphism of the gene coding for apolipoprotein E (apoE) is already known to be associated with a differential susceptibility to clinical coronary heart disease (CHD).^{2 3 4 5} Risk is increased 40% in carriers of the 4 allele compared with carriers of the most common apoE genotype, 33, or carriers of the 2 allele.⁵ Some studies also suggest that 4 carriers are particularly prone to develop disseminated coronary lesions and to die from CHD.^{6 7 8 9 10} The biochemical mechanisms underlying these relationships are unclear, but they may relate to the dysfunction of the encoded apoE4 isoform in lipoprotein metabolism and the increased serum concentrations of cholesterol and triglycerides.^{2 11 12 13}

We determined apoE genotypes in a subset of Danish and Finnish participants in the Scandinavian Simvastatin Survival Study to test 2 null hypotheses. The first was that risk of death or a recurrent major coronary event during the follow-up of survivors of myocardial infarction (MI) is independent of the apoE genotype. The second was that the benefit of treatment with simvastatin is independent of apoE genotype.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patients and Study Design
The design of the Scandinavian Simvastatin Survival Study has been described previously.¹⁴ Briefly, men and women aged 35 to 70 years with a history of MI or angina, serum total cholesterol concentrations in the range of 5.5 to 8.0 mmol/L, and serum triglyceride levels 2.5 mmol/L, after dietary advice, were randomized to receive either placebo or simvastatin. The initial dosage was 20 mg per day, which was raised to 40 mg per day if serum total cholesterol exceeded 5.2 mmol/L at 6 or 18 weeks. The patients were followed for a median period of 5.4 years. The primary study end point was death from any cause, and the secondary end point was a major coronary event (MCE). The MCEs included coronary death, nonfatal definite or probable MI, silent MI, or resuscitated cardiac arrest.

We used data from the Danish and Finnish patients who had been included with a history of MI as a qualifying diagnosis and from whom blood samples were available for apoE genotyping (61% of the 713 Danish patients and 61% of the 868 Finnish patients). Median follow-up time in this subset of patients was 5.5 years (range, 5.1 to 6.0 years for those surviving). Danish and Finnish patients differed in some respects. Thus, 55% percent of the Danes and only 48% of the Finns were 60 to 70 years of age, 40% of the Danes and 28% of the Finns had concurrent angina, and 41% of the Danes and 24% of the Finns were current smokers. However, 28% of the Finns and only 14% of the Danes had a history of hypertension, and 7% of the Finns and 3% of the Danes had diabetes.

Measurement of Apolipoproteins
Serum concentrations of apolipoprotein A-I (apoA-I) and B (apoB) were measured by immunoturbidimetry using test kits with antisera and standards from Orion Diagnostics. Serum concentrations of lipoprotein(a) (Lp[a]) were measured using immunoradiometric assay test kits from Pharmacia Diagnostics.¹⁵

ApoE Genotyping
Genotypes in the Danish patients were determined using the method of Hixson and Vernier,¹⁶ as previously described.¹⁷ The genotypes in Finnish patients were determined from protein phenotypes using isoelectric focusing.¹⁸ We defined 4 carriers as patients with apoE genotypes 24, 34, or 44.

Statistical Methods
All data were analyzed according to the intention-to-treat principle, and P0.05 (2-sided) was regarded as significant. Risk (hazard) ratios with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.^{19 20} We used backward stepwise variable selection with removal testing, which was based on the probability of the likelihood-ratio statistic to identify variables associated with prognosis in patients on placebo (death, coronary death, or MCE). P<0.05 was used as a criterion for both entry and removal of variables. The initial model included 4-carrier status, nationality, sex, age group (<60 or 60 to 70 years of age at time of randomization), angina pectoris, hypertension, claudication, diabetes, and smoking at baseline, as well as baseline levels of high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apoA-I, apoB, and Lp(a).

In the resulting model, LDL cholesterol and Lp(a) were dichotomized to estimate risk ratios associated with high levels. The cut-off value was 4.75 mmol/L for LDL cholesterol (the mean in all patients) and 30 mg/dL for Lp(a), which is a conventionally used threshold value and also the lower limit for the upper tertile in all patients. To assess the significance of the possible modification of risk ratios for 4 carriers across strata by nationality, age, sex, angina, smoking, LDL levels, and Lp(a) levels, we used models with forward selection of interaction terms that were based on the probability of the likelihood-ratio statistic. To examine the influence of baseline plasma lipoprotein levels on the risk ratio estimates for 4 carriers, we used models with LDL cholesterol (or apoB), high-density lipoprotein cholesterol (or apoA-I), and triglyceride forced into the models.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics and Number of End Points in the 966 MI Patients
Table 1 shows the distribution of patients by apoE genotype and the baseline characteristics of the patients. No significant differences existed in the characteristics of patients with and without the 4 allele. Numbers of deaths, split into noncoronary and coronary deaths, and numbers of MCEs during follow-up in patients treated with placebo or simvastatin are shown in Table 2.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of MI Patients With Different ApoE Genotypes

View this table: [in this window] [in a new window]   Table 2. Numbers of Deaths and Numbers of Patients With 1 MCE, Grouped by Treatment and ApoE Genotype

ApoE Genotype and Prognosis in 478 MI Patients on Placebo
Figure 1 shows Kaplan-Meier survival curves for patients with and without the 4 allele. The crude risk ratio for 4 carriers was 1.8 (95% CI, 1.1 to 3.1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves for all-cause mortality in MI patients with and without 4 allele who were treated with placebo.

Table 3 shows the results of multivariate analyses. Variables in the models emerged from backward selections with either death, coronary death, or MCE as outcomes. The 4 allele, male sex, age>60 years, concurrent angina, diabetes, and high Lp(a) levels were all associated with total mortality risk ratios >1.5, whereas the effects of smoking and high LDL cholesterol were smaller and not significant. The same pattern was seen for coronary deaths, except that male sex and age seemed to be less important and diabetes and smoking more important. Risk ratios for a MCE were generally lower than for death, except for high LDL cholesterol. Only this trait, male sex, and diabetes were significant predictors of a MCE.

View this table: [in this window] [in a new window]   Table 3. Results of Multivariate Cox Regression Analyses of Data From Patients Treated With Placebo: Estimated Relative Hazards Associated With Determinants of Death, Coronary Death, or a MCE

No significant interactions existed between 4-carrier status and the other variables for either outcome (death or MCE), although the size of a coefficient for an 4 carrier by smoking interaction approached significance for death (P=0.010). Hence, when analyses were split by smoking status, the multivariate mortality risk ratio for 4 carriers was 2.9 (95% CI, 1.4 to 6.1) in nonsmokers and 1.2 (95% CI, 0.5 to 2.8) in smokers. Nationality was not a determinant of risk. Nevertheless, we forced nationality into the multivariate models and tested for interaction with 4-carrier status. The probability values for interaction under the null hypotheses were 0.44, 0.75, and 0.65 with death, coronary death, and MCE as the outcome, respectively, which indicates the homogeneity of the findings for 4 carriers among Danes and Finns.

A total of 45% of the patients were either 4 carriers or had high baseline Lp(a) levels. As shown in Table 4, these patients had an adjusted mortality risk ratio of 2.3 (95% CI, 1.1 to 4.5) compared with patients who were not 4 carriers and who had low Lp(a) levels. The smaller group of patients (13%) who were 4 carriers and who had high Lp(a) levels had a risk ratio of 3.7 (95% CI, 1.7 to 8.1). Corresponding risk ratios for coronary death were 1.9 (95% CI, 0.9 to 4.3) for 4 or Lp(a) and 3.3 (95% CI, 1.3 to 8.1) for 4+Lp(a), respectively; for MCEs, they were 1.1 (95% CI, 0.8 to 1.7) for 4 or Lp(a) and 1.5 (95% CI, 0.9 to 2.4) for 4+Lp(a), respectively.

View this table: [in this window] [in a new window]   Table 4. Adjusted Relative Mortality Hazard Ratios by 4-Carrier Status and Lp(a) Levels in Patients Treated With Placebo

ApoE Genotype and Effect of Simvastatin on Mortality Hazard
The survival of treated patients who were or were not 4 carriers was nearly the same (Figure 2). Comparisons with the data in Figure 1, therefore, suggest that treatment is particularly beneficial for 4 carriers.

View larger version (14K): [in this window] [in a new window]   Figure 2. Kaplan-Meier curves for all-cause mortality in MI patients with and without 4 allele who were treated with simvastatin.

The results shown in Table 5 lend further support to this concept. Compared with patients on placebo, the risk of dying was reduced to 0.49 in all treated MI patients. The risk was reduced to 0.33 in 4 carriers, which was half the value in patients without 4 (P=0.21 for treatment by apoE genotype interaction). As shown in Figure 3, the apparent difference in risk reduction was not associated with differences in LDL cholesterol response to treatment. We also examined the effect of treatment on mortality risk in the 4 groups of patients defined by 4-carrier status and/or high Lp(a) levels (Table 5). Mortality was reduced to the same low level (5% to 7%) in all groups (data not shown); thus, treatment reduced mortality risk by 13% in patients who were not 4 carriers and who had low Lp(a) levels, by 50% in patients who either were 4 carriers or had high Lp(a) levels, and by 80% in patients who had both risk factors (P=0.24 for treatment by group interaction).

View this table: [in this window] [in a new window]   Table 5. Adjusted Relative Mortality Hazard Ratios due to Treatment With Simvastatin: Role of 4-Carrier Status and Lp(a) Level

View larger version (29K): [in this window] [in a new window]   Figure 3. LDL cholesterol levels in 4 carriers (filled symbols) and non-4 carriers (open symbols) during first 24 weeks of treatment with placebo (circles) or simvastatin (squares).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study shows (1) that MI patients carrying the 4 allele have about twice the risk of dying during a follow-up period of 5.5 years compared with patients who are not 4 carriers and (2) that these 4 carriers seem to benefit particularly well from treatment with simvastatin. To our knowledge, 4 is, therefore, the first example of a common genetic marker that identifies a subgroup of coronary patients that is simultaneously at a higher risk of death and particularly prone to benefit from preventive treatment. Findings of this kind have been predicted by genetic epidemiological research in this field.^{21 22 23}

The association of 4 with risk of death was mainly due to an increased risk of coronary death, the most common cause of death in these patients. Nevertheless, an excess of 5 noncoronary deaths among 4 carriers also contributed to the increase in the mortality risk ratio.

Risk of Death Versus MCE
The increased risk of (coronary) death due to 4 was not accompanied by an increased risk of a MCE, which in most cases was recurrence of MI. However, this finding was not particular to 4; it also pertained to age, concurrent angina, diabetes, smoking, and Lp(a) levels as predictors (Table 3).

The possibility that the association of 4 with mortality could be a chance finding due to small numbers is unlikely because it was consistent across strata by nationality, sex, and the other variables. We also considered whether the estimated risk ratio for a MCE was biased toward unity. This could happen, for instance, if some cases of nonfatal events were falsely diagnosed and others were missed, ie, so-called nondifferential misclassification.²⁴ However, misclassification was unlikely to have occurred to a degree that could negate a true risk ratio of 2 for a nonfatal MCE.

Possible Reasons Why 4 Specifically Associated With Risk of Death
We then considered whether the discordant findings for risks of fatal and nonfatal coronary events could be due to the involvement of apoE in some particularly malignant pathogenic mechanism that increased the risk of dying. Independent epidemiological evidence supports this concept. A follow-up study of individuals initially free of clinical CHD suggested that 4 carriers had a particularly high risk of fatal events.⁷ Moreover, some angiographic studies of CHD patients have shown that 4 carriers more often have disseminated and severe coronary lesions than noncarriers.^{6 8 10}

The progression of coronary lesions is a strong predictor of coronary events, especially fatal events,²⁵ and the rupture of a vulnerable plaque often precedes occlusive coronary thrombosis and death.^{26 27} The evidence for an association of 4 with increased progression rate is weak, however,^{28 29 30} and we are not aware of studies investigating the association of apoE genotype and the occurrence of vulnerable plaques. It is, nevertheless, possible that the ability of simvastatin treatment to abolish the increased mortality risk in 4 carriers relates to the inhibition of the progression of lesions and/or the stabilization of vulnerable plaques.³¹

Increased risk and the beneficial effect of simvastatin could be due to the higher serum LDL cholesterol and triglyceride levels found in patients with 4 than in patients with other genotypes, as suggested by earlier studies.^{2 12} However, 3 observations make this explanation unlikely and suggest instead that the effect of 4 may involve pathogenic mechanisms unrelated to serum lipoproteins. (1) Baseline lipid levels did not differ between apoE genotypes (Table 1), possibly because the criteria for recruiting patients necessarily resulted in truncated distributions of the variables or because prerandomization dietary treatment could have reduced the differences.³² (2) The inclusion of lipid variables in multivariate models did not influence the estimated mortality risk ratio in 4 carriers. (3) 4 carriers and patients with other genotypes were equally responsive to simvastatin treatment in terms of LDL cholesterol lowering (Figure 3). Other studies have indicated that 4 carriers, if anything, are less responsive to statin treatment than other individuals.^{33 34} Therefore, no evidence linked differential risk reduction to a corresponding differential LDL cholesterol lowering.

ApoE plays roles in neuronal function and, possibly, also in platelet function and coagulation.^{35 36 37 38 39} Hence, the pathogenic mechanisms involved could relate to coronary vascular reactivity and thrombogenesis.

Effects of 4 and Lp(a)
A study of all participants in the Scandinavian Simvastatin Survival Study showed that the baseline serum Lp(a) level was associated with a risk of death and MCE.¹⁵ In the present study, serum Lp(a) levels >30 mg/dL were associated with a 2-fold increased mortality risk. High Lp(a) levels are mainly found in carriers of small KpnI alleles at the apolipoprotein(a) gene; this is a relatively constant trait in these individuals.⁴⁰ In this study, it seemed that the presence or absence of 4 and high or low Lp(a) levels could be combined to define 3 groups of patients with markedly different risks of death when treated with placebo (Table 4). With simvastatin, however, the same low mortality rates were obtained in all groups. Hence, the combination of apoE genotyping and the measurement of serum Lp(a) levels may be used to identify groups of patients who are genetically vulnerable and particularly likely to benefit from treatment.

Conclusions
The 4 allele has a lethal effect in survivors of MI that seems unrelated to the lipid variables examined in this study. Nonetheless, it can be abolished by treatment with simvastatin. Although more studies are clearly warranted, our findings demonstrate that molecular genetic information can be used to improve the clinical management of patients with a common disease.

	Acknowledgments

 
The Scandinavian Simvastatin Survival Study was supported by a grant from Merck Research Laboratories, Rahway, New Jersey. We thank Thomas B. Cook of Merck Research Laboratories for supplying data files for the study and Professor Kalevi Pyörälä of the University of Kuopio and Professor John Kjekshus of the University of Oslo for helpful comments and suggestions during the preparation of the manuscript. We also thank Gitte Glistrup Nielsen, Anette Stenderup, and Pia Hornbek for their excellent assistance in the laboratory.

Received July 2, 1999; revision received September 25, 1999; accepted October 11, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Rosenthal N, Schwartz RS. In search of perverse polymorphisms. N Engl J Med. 1998;338:122–124.[Free Full Text]
   
2. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8:1–21.[Abstract/Free Full Text]
   
3. Hixson JE. Apolipoprotein E polymorphism affect atherosclerosis in young males. Arterioscler Thromb. 1991;11:1237–1244.[Abstract/Free Full Text]
   
4. de Knijff P, Havekes LM. Apolipoprotein E as a risk factor for coronary heart disease: a genetic and molecular biology approach. Curr Opin Lipidol. 1996;7:59–63.[Medline] [Order article via Infotrieve]
   
5. Wilson PWF, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Arterioscler Thromb Vasc Biol. 1996;16:1250–1255.[Abstract/Free Full Text]
   
6. Köhler E, Bentrup A, Funke H, Sandkamp M, Schulte H, Assmann G. Untersuchungen zur Beziehung zwischen Lipidstoffwechselstörungen und Erstmanifestationsalter der koronaren Herzkrankheit (KHK). Z Kardiol. 1992;81:354–360.[Medline] [Order article via Infotrieve]
   
7. Eichner JE, Kuller LH, Orchard TJ, Grandits GA, McCallum LM, Ferrell RE, Neaton JD. Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary heart disease. Am J Cardiol. 1993;71:160–165.[Medline] [Order article via Infotrieve]
   
8. Lehtinen S, Lehtimaki T, Sisto T, Salenius JP, Nikkila M, Jokela H, Koivula T, Ebeling F, Ehnholm C. Apolipoprotein E polymorphism, serum lipids, myocardial infarction and severity of angiographically verified coronary artery disease in men and women. Atherosclerosis. 1995;114:83–91.[Medline] [Order article via Infotrieve]
   
9. Stengård JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995;91:265–269.[Abstract/Free Full Text]
   
10. Wang XL, McCredie RM, Wilcken DEL. Polymorphisms of the apolipoprotein E gene and severity of coronary artery disease defined by angiography. Arterioscler Thromb Vasc Biol. 1995;15:1030–1034.[Abstract/Free Full Text]
    
11. Utermann G. Apolipoprotein E polymorphism in health and disease. Am Heart J. 1987;113:433–440.[Medline] [Order article via Infotrieve]
    
12. Dallongeville J, Lussier Cacan S, Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. J Lipid Res. 1992;33:447–454.[Abstract]
    
13. Weisgraber KH. Apolipoprotein E: structure-function relationships. In: Schumaker VN, ed. Advances in Protein Chemistry. Vol 45. New York: Academic Press; 1994:249–302.
    
14. Scandinavian Simvastatin Survival Study Group. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol. 1993;71:393–400.[Medline] [Order article via Infotrieve]
    
15. Berg K, Dahlen G, Christophersen B, Cook T, Kjekshus J, Pedersen T. Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study. Clin Genet. 1997;52:254–261.[Medline] [Order article via Infotrieve]
    
16. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548.[Abstract]
    
17. Hansen PS, Gerdes LU, Klausen IC, Gregersen N, Faergeman O. Genotyping compared with protein phenotyping of the common apolipoprotein E polymorphism. Clin Chim Acta. 1994;224:131–137.[Medline] [Order article via Infotrieve]
    
18. Ehnholm C, Lukka M, Kuusi T, Nikkila E, Utermann G. Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res. 1986;27:227–235.[Abstract]
    
19. Cox DR. Regression models and life-tables. J R Stat Soc. 1972;34:187–202.
    
20. Kleinbaum DG. Survival Analysis. A Self-Learning Text. New York: Springer-Verlag; 1996.
    
21. Goldbourt U, Neufeld HN. Genetic aspects of arteriosclerosis. Arteriosclerosis. 1986;6:357–377.[Abstract/Free Full Text]
    
22. Berg K. Impact of medical genetics on research and practices in the area of cardiovascular disease. Clin Genet. 1989;36:299–312.[Medline] [Order article via Infotrieve]
    
23. Sing CF, Moll PP. Genetics of variability of CHD risk. Int J Epidemiol. 1989;18:S183–S195.[Abstract]
    
24. Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia, Pa: Lippincott-Raven Publishers; 1998:127–132.
    
25. Waters D, Craven TE, Lespérance J. Prognostic significance of progression of coronary atherosclerosis. Circulation. 1993;87:1067–1075.[Abstract/Free Full Text]
    
26. Schroeder AP, Falk E. Vulnerable and dangerous coronary plaques. Atherosclerosis. 1995;118(suppl):S141–S149.
    
27. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. Circulation. 1996;94:2013–2020.[Free Full Text]
    
28. Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 1993;88:2762–2770.[Abstract/Free Full Text]
    
29. Damaraju S, Yu QT, Safavi F, Marian AJ. Apolipoprotein epsilon 4 is not a genetic risk factor for coronary artery disease or restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 1995;75:1181–1183.[Medline] [Order article via Infotrieve]
    
30. van Bockxmeer FM, Mamotte CDS, Gibbons FA, Burke V, Taylor RR. Angiotensin-converting enzyme and apolipoprotein E genotypes and restenosis after coronary angioplasty. Circulation. 1995;92:2066–2071.[Abstract/Free Full Text]
    
31. Kinlay S, Selwyn AP, Delagrange D, Creager MA, Libby P, Ganz P. Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points. Curr Opin Lipidol. 1996;7:389–397.[Medline] [Order article via Infotrieve]
    
32. Ordovas JM, Lopez-Miranda J, Mata P, Perez-Jimenez F, Lichtenstein AH, Schaefer EJ. Gene-diet interaction in determining plasma lipid response to dietary intervention. Atherosclerosis. 1996;118(suppl):S11–S27.
    
33. Ordovas JM, Lopez Miranda J, Perez Jimenez F, Rodriguez C, Park JS, Cole T, Schaefer EJ. Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy. Atherosclerosis. 1995;113:157–166.[Medline] [Order article via Infotrieve]
    
34. Kobayashi T, Homma Y, Handa S, Nakamura H. Influence of apolipoprotein E phenotype on changes in plasma levels of low-density lipoprotein-cholesterol and apolipoprotein B due to the effects of simvastatin. Nutr Metab Cardiovasc Dis. 1998;8:358–364.
    
35. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–630.[Abstract/Free Full Text]
    
36. Weisgraber KH, Roses AD, Strittmatter WJ. The role of apolipoprotein E in the nervous system. Curr Opin Lipidol. 1994;5:110–116.[Medline] [Order article via Infotrieve]
    
37. Mazzone T. Apolipoprotein E secretion by macrophages: its potential physiological functions. Curr Opin Lipidol. 1996;7:303–307.[Medline] [Order article via Infotrieve]
    
38. Higashihara M, Kinoshita M, Teramoto T, Kume S, Kurokawa K. The role of apoE in inhibitory effects of apoE-rich HDL on platelet function. FEBS Lett. 1991;282:82–86.[Medline] [Order article via Infotrieve]
    
39. Loktionov A, Bingham SA, Vorster H, Jerling JC, Runswick SA, Cummings JH. Apolipoprotein E genotype modulates the effect of black tea drinking on blood lipids and blood coagulation factors: a pilot study. Br J Nutr. 1998;79:133–139.[Medline] [Order article via Infotrieve]
    
40. Lemming L, Klausen IC, Gerdes LU, Hansen PS, Faergeman O. Apolipoprotein(a) genotypes in a Scandinavian population: allele frequencies, correlation to apolipoprotein(a) phenotypes and lipoprotein(a) concentrations. Nutr Metab Cardiovasc Dis. 1997;7:1–7.
    

This article has been cited by other articles:

				S. B. Damani and E. J. Topol Future Use of Genomics in Coronary Artery Disease J. Am. Coll. Cardiol., November 13, 2007; 50(20): 1933 - 1940. [Abstract] [Full Text] [PDF]

				A. M. Bennet, E. Di Angelantonio, Z. Ye, F. Wensley, A. Dahlin, A. Ahlbom, B. Keavney, R. Collins, B. Wiman, U. de Faire, et al. Association of Apolipoprotein E Genotypes With Lipid Levels and Coronary Risk JAMA, September 19, 2007; 298(11): 1300 - 1311. [Abstract] [Full Text] [PDF]

				B. D. Chiodini, M. G. Franzosi, S. Barlera, S. Signorini, C. M. Lewis, A. D'Orazio, P. Mocarelli, E. Nicolis, R. Marchioli, G. Tognoni, et al. Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study Eur. Heart J., August 2, 2007; 28(16): 1977 - 1983. [Abstract] [Full Text] [PDF]

				K. M. Momary Cardiovascular Pharmacogenomics Journal of Pharmacy Practice, June 1, 2007; 20(3): 265 - 276. [Abstract] [PDF]

				O. A. Iakoubova, C. H. Tong, A. P. Chokkalingam, C. M. Rowland, T. G. Kirchgessner, J. Z. Louie, L. M. Ploughman, M. S. Sabatine, H. Campos, J. J. Catanese, et al. Asp92Asn Polymorphism in the Myeloid IgA Fc Receptor Is Associated With Myocardial Infarction in Two Disparate Populations: CARE and WOSCOPS Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2763 - 2768. [Abstract] [Full Text] [PDF]

				E. Anuurad, J. Rubin, G. Lu, T. A. Pearson, S. Holleran, R. Ramakrishnan, and L. Berglund Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol J. Lipid Res., November 1, 2006; 47(11): 2475 - 2481. [Abstract] [Full Text] [PDF]

				J R Ortlepp, M Pillich, V Mevissen, C Krantz, M Kimmel, R Autschbach, G Langebartels, J Erdmann, R Hoffmann, and K Zerres APOE alleles are not associated with calcific aortic stenosis Heart, October 1, 2006; 92(10): 1463 - 1466. [Abstract] [Full Text] [PDF]

				M. S. Sabatine, J. G. Seidman, and C. E. Seidman Cardiovascular Genomics Circulation, March 21, 2006; 113(11): e450 - e455. [Full Text] [PDF]

				G. D. Kolovou, K. K. Anagnostopoulou, D. P. Mikhailidis, D. B. Panagiotakos, N. D. Pilatis, M. A. Cariolou, N. Yiannakouris, D. Degiannis, G. Stavridis, and D. V. Cokkinos Association of Apolipoprotein E Genotype with Early Onset of Coronary Heart Disease in Greek Men Angiology, November 1, 2005; 56(6): 663 - 670. [Abstract] [PDF]

				E. J. Topol The Genomic Basis of Myocardial Infarction J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1456 - 1465. [Full Text] [PDF]

				R. M. Lane and M. R. Farlow Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease J. Lipid Res., May 1, 2005; 46(5): 949 - 968. [Abstract] [Full Text] [PDF]

				J. A. Johnson and L. H. Cavallari Cardiovascular pharmacogenomics Exp Physiol, May 1, 2005; 90(3): 283 - 289. [Abstract] [Full Text] [PDF]

				J. W. Stephens, M. M. Sozen, R. A. Whittall, M. J. Caslake, D. Bedford, J. Acharya, S. J. Hurel, and S. E. Humphries Three Novel Mutations in the Apolipoprotein E Gene in a Sample of Individuals with Type 2 Diabetes Mellitus Clin. Chem., January 1, 2005; 51(1): 119 - 124. [Abstract] [Full Text] [PDF]

				W. Koch, J. Mehilli, A. Pfeufer, A. Schomig, and A. Kastrati Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting J. Lipid Res., December 1, 2004; 45(12): 2221 - 2226. [Abstract] [Full Text] [PDF]

				I. Zineh Genetic Polymorphisms and Statin Therapy JAMA, September 15, 2004; 292(11): 1302 - 1303. [Full Text] [PDF]

				Y. Song, M. J. Stampfer, and S. Liu Meta-Analysis: Apolipoprotein E Genotypes and Risk for Coronary Heart Disease Ann Intern Med, July 20, 2004; 141(2): 137 - 147. [Abstract] [Full Text] [PDF]

				O Faergeman Evolution of statin therapy: an ongoing story Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A3 - A7. [Abstract] [Full Text] [PDF]

				C Aucan, A J Walley, and A V S Hill Common apolipoprotein E polymorphisms and risk of clinical malaria in the Gambia J. Med. Genet., January 1, 2004; 41(1): 21 - 24. [Full Text] [PDF]

				S. I. Malloy, M. K. Altenburg, C. Knouff, L. Lanningham-Foster, J. S. Parks, and N. Maeda Harmful Effects of Increased LDLR Expression in Mice With Human APOE*4 But Not APOE*3 Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 91 - 97. [Abstract] [Full Text] [PDF]

				E. G. Nabel Cardiovascular Disease N. Engl. J. Med., July 3, 2003; 349(1): 60 - 72. [Full Text] [PDF]

				G. L. Vega, M. F. Weiner, A. M. Lipton, K. von Bergmann, D. Lutjohann, C. Moore, and D. Svetlik Reduction in Levels of 24S-Hydroxycholesterol by Statin Treatment in Patients With Alzheimer Disease Arch Neurol, April 1, 2003; 60(4): 510 - 515. [Abstract] [Full Text] [PDF]

				J. L. Anderson, J. F. Carlquist, B. D. Home, and J. B. Muhlestein Cardiovascular Pharmacogenomics: Current Status, Future Prospects Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 71 - 83. [Abstract] [PDF]

				W. E. Evans and H. L. McLeod Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects N. Engl. J. Med., February 6, 2003; 348(6): 538 - 549. [Full Text] [PDF]

<