American Journal of Epidemiology Vol. 155, No. 6 : 487-495
Copyright © 2002 by The Johns Hopkins University School of Hygiene and Public Health
HUMAN GENOME EPIDEMIOLOGY (HuGE) REVIEW |
Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review
1 Department of Biostatistics and Epidemiology, College of Public Health, University of Oklahoma, Oklahoma City, OK.
2 Pathology Department, College of Medicine, University of Oklahoma, Oklahoma City, OK.
ABSTRACT
This review examines the association between the apolipoprotein (apo) 
gene polymorphism (or its protein product (apo E)), metabolic regulation of cholesterol, and cardiovascular disease. The apo gene is located at chromosome 19q13.2. Among the variants of this gene, alleles *2, *3, and *4 constitute the common polymorphism found in most populations. Of these variants, apo *3 is the most frequent (>60%) in all populations studied. The polymorphism has functional effects on lipoprotein metabolism mediated through the hepatic binding, uptake, and catabolism of chylomicrons, chylomicron remnants, very low density lipoprotein (VLDL), and high density lipoprotein subspecies. Apo E is the primary ligand for two receptors, the low density lipoprotein (LDL) receptor (also known as the B/E receptor) found on the liver and other tissues and an apo E-specific receptor found on the liver. The coordinate interaction of these lipoprotein complexes with their receptors forms the basis for the metabolic regulation of cholesterol. Allelic variation in apo is consistently associated with plasma concentrations of total cholesterol, LDL cholesterol, and apo B (the major protein of LDL, VLDL, and chylomicrons). Apo has been studied in disorders associated with elevated cholesterol levels or lipid derangements (i.e., hyperlipoproteinemia type III, coronary heart disease, strokes, peripheral artery disease, and diabetes mellitus). The apo genotype yields poor predictive values when screening for clinically defined atherosclerosis despite positive, but modest associations with plaque and coronary heart disease outcomes. In addition to genotype-phenotype associations with vascular disease, the alleles and isoforms of apo have been related to dementias, most commonly Alzheimer's disease.
apolipoproteins E; cardiovascular diseases; epidemiology; genetics
Abbreviations: apo, apolipoprotein; CHD, coronary heart disease; CI, confidence interval; LDL, low density lipoprotein; VLDL, very low density lipoprotein
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|
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|
 |
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|
|
|
|
 |
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|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
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|
|
 |
|
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|
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|
|
|
|
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|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
K. E. North, H. H. H. Goring, S. A. Cole, V. P. Diego, L. Almasy, S. Laston, T. Cantu, B. V. Howard, E. T. Lee, L. G. Best, et al. Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study J. Lipid Res., January 1, 2006; 47(1): 59 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ramaswamy, Q. Xu, Y. Huang, and K. H. Weisgraber Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain J. Neurosci., November 16, 2005; 25(46): 10658 - 10663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. S. Descamps, M. Bruniaux, P.-F. Guilmot, R. Tonglet, and F. R. Heller Lipoprotein metabolism of pregnant women is associated with both their genetic polymorphisms and those of their newborn children J. Lipid Res., November 1, 2005; 46(11): 2405 - 2414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Kolovou, K. K. Anagnostopoulou, K. D. Salpea, D. B. Panagiotakos, I. S. Hoursalas, M. A. Cariolou, K. Koniavitou, and D. V. Cokkinos Apolipoprotein E Genotype in Matched Men and Women with Coronary Heart Disease Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 391 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Yip, A. C. McKee, R. C. Green, J. Wells, H. Young, L. A. Cupples, and L. A. Farrer APOE, vascular pathology, and the AD brain Neurology, July 26, 2005; 65(2): 259 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, M. H. Picard, E. Vasile, Y. Zhu, R. L. Raffai, K. H. Weisgraber, and M. Krieger Diet-Induced Occlusive Coronary Atherosclerosis, Myocardial Infarction, Cardiac Dysfunction, and Premature Death in Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein ER61 Mice Circulation, June 28, 2005; 111(25): 3457 - 3464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.A. Schneider, J.L. Bienias, R.S. Wilson, E. Berry-Kravis, D.A. Evans, and D.A. Bennett The Apolipoprotein E {epsilon}4 Allele Increases the Odds of Chronic Cerebral Infarction Detected at Autopsy in Older Persons Stroke, May 1, 2005; 36(5): 954 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Grainger, J. Reckless, and E. McKilligin Apolipoprotein E Modulates Clearance of Apoptotic Bodies In Vitro and In Vivo, Resulting in a Systemic Proinflammatory State in Apolipoprotein E-Deficient Mice J. Immunol., November 15, 2004; 173(10): 6366 - 6375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G Manton, X. Gu, H. Huang, and M. Kovtun Fuzzy set analyses of genetic determinants of health and disability status Statistical Methods in Medical Research, October 1, 2004; 13(5): 395 - 408. [Abstract] [PDF]
|
|
|
|
|
|
M. A. Austin, C. M. Hutter, R. L. Zimmern, and S. E. Humphries Familial Hypercholesterolemia and Coronary Heart Disease: A HuGE Association Review Am. J. Epidemiol., September 1, 2004; 160(5): 421 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Manolio, E. Boerwinkle, C. J. O'Donnell, and A. F. Wilson Genetics of Ultrasonographic Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1567 - 1577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [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]
|
|
|
|
 |
|
 C. Winkelman Genomics: What Every Critical Care Nurse Needs to Know About the Genetic Contribution to Critical Illness Crit. Care Nurse, June 1, 2004; 24(3): 34 - 45. [Full Text] [PDF]
|
|
|
|
 |
|
 M Zetterberg, H Zetterberg, M Palmer, L Rymo, K Blennow, G Tasa, E Juronen, S Veromann, P Teesalu, J-O Karlsson, et al. Apolipoprotein E polymorphism in patients with cataract Br J Ophthalmol, May 1, 2004; 88(5): 716 - 718. [Full Text] [PDF]
|
|
|
|
|
|
T. M. Doherty, L. A. Fitzpatrick, A. Shaheen, T. B. Rajavashisth, and R. C. Detrano Genetic Determinants of Arterial Calcification Associated With Atherosclerosis Mayo Clin. Proc., February 1, 2004; 79(2): 197 - 210. [Abstract] [PDF]
|
|
|
|
|
|
D. C. Ewbank The APOE Gene and Differences in Life Expectancy in Europe J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2004; 59(1): B16 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.F. Kinane and T.C. Hart GENES AND GENE POLYMORPHISMS ASSOCIATED WITH PERIODONTAL DISEASE Critical Reviews in Oral Biology & Medicine, November 1, 2003; 14(6): 430 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Niino, S Kikuchi, T Fukazawa, I Yabe, and K Tashiro Polymorphisms of apolipoprotein E and Japanese patients with multiple sclerosis Multiple Sclerosis, August 1, 2003; 9(4): 382 - 386. [Abstract] [PDF]
|
|
|
|
 |
|
 C Infante-Rivard, E Levy, G-E Rivard, M Guiguet, and J-C Feoli-Fonseca Small babies receive the cardiovascular protective apolipoprotein {varepsilon}2 allele less frequently than expected J. Med. Genet., August 1, 2003; 40(8): 626 - 629. [Full Text]
|
|
|
|
|
|
S. Horiuchi, C. E. Finch, F. Mesle, and J. Vallin Differential Patterns of Age-Related Mortality Increase in Middle Age and Old Age J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2003; 58(6): B495 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
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|
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