Arteriosclerosis, Vol 8, 1-21, Copyright © 1988 by American Heart Association

ARTICLES

Apolipoprotein E polymorphism and atherosclerosis

J Davignon, RE Gregg and CF Sing
Department of Lipid Metabolism and Atherosclerosis Research, Clinical Research Institute of Montreal, Quebec, Canada.

The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.

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				M. A. Austin Ethical Issues in Human Genome Epidemiology: A Case Study Based on The Japanese American Family Study in Seattle, Washington Am. J. Epidemiol., April 1, 2002; 155(7): 585 - 592. [Abstract] [Full Text] [PDF]

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				D. Corella, M. Guillen, C. Saiz, O. Portoles, A. Sabater, J. Folch, and J. M. Ordovas Associations of LPL and APOC3 gene polymorphisms on plasma lipids in a Mediterranean population: interaction with tobacco smoking and the APOE locus J. Lipid Res., March 1, 2002; 43(3): 416 - 427. [Abstract] [Full Text] [PDF]

				L. Rask-Nissila, E. Jokinen, J. Viikari, A. Tammi, T. Ronnemaa, J. Marniemi, P. Salo, T. Routi, H. Helenius, I. Valimaki, et al. Impact of Dietary Intervention, Sex, and Apolipoprotein E Phenotype on Tracking of Serum Lipids and Apolipoproteins in 1- to 5-Year-Old Children: The Special Turku Coronary Risk Factor Intervention Project (STRIP) Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 492 - 498. [Abstract] [Full Text] [PDF]

				M. M. Murphy, E. Vilella, S. Ceruelo, L. Figuera, M. Sanchez, J. Camps, G. Cuco, N. Ferre, A. Labad, N. Tasevska, et al. The MTHFR C677T, APOE, and PON55 Gene Polymorphisms Show Relevant Interactions with Cardiovascular Risk Factors Clin. Chem., February 1, 2002; 48(2): 372 - 375. [Full Text] [PDF]

				J. D. Harris, I. R. Graham, S. Schepelmann, A. K. Stannard, M. L. Roberts, B. L. Hodges, V. Hill, A. Amalfitano, D. G. Hassall, J. S. Owen, et al. Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation [E1-, E3-, polymerase-] adenovirus vector expressing human apoE Hum. Mol. Genet., January 1, 2002; 11(1): 43 - 58. [Abstract] [Full Text] [PDF]

				M. S. Bernstein, M. C. Costanza, R. W. James, M. A. Morris, F. Cambien, S. Raoux, and A. Morabia Physical Activity May Modulate Effects of ApoE Genotype on Lipid Profile Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 133 - 140. [Abstract] [Full Text] [PDF]

				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]

				H. Vosper, L. Patel, T. L. Graham, G. A. Khoudoli, A. Hill, C. H. Macphee, I. Pinto, S. A. Smith, K. E. Suckling, C. R. Wolf, et al. The Peroxisome Proliferator-activated Receptor delta Promotes Lipid Accumulation in Human Macrophages J. Biol. Chem., November 16, 2001; 276(47): 44258 - 44265. [Abstract] [Full Text] [PDF]

				N. Schupf, D. Kapell, B. Nightingale, J. H. Lee, J. Mohlenhoff, S. Bewley, R. Ottman, and R. Mayeux Specificity of the fivefold increase in AD in mothers of adults with Down syndrome Neurology, September 25, 2001; 57(6): 979 - 984. [Abstract] [Full Text] [PDF]

				R. L. Raffai, L.-M. Dong, R. V. Farese Jr., and K. H. Weisgraber Introduction of human apolipoprotein E4 ""domain interaction"" into mouse apolipoprotein E PNAS, September 5, 2001; (2001) 201279298. [Abstract] [Full Text] [PDF]

				A.J.C. Slooter, M. L. Bots, L. M. Havekes, A. I. del Sol, M. Cruts, D. E. Grobbee, A. Hofman, C. Van Broeckhoven, J.C.M. Witteman, and C. M. van Duijn Apolipoprotein E and Carotid Artery Atherosclerosis: The Rotterdam Study Stroke, September 1, 2001; 32(9): 1947 - 1952. [Abstract] [Full Text] [PDF]

				M. Kivipelto, E.-L. Helkala, M. P Laakso, T. Hanninen, M. Hallikainen, K. Alhainen, H. Soininen, J. Tuomilehto, and A. Nissinen Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study BMJ, June 16, 2001; 322(7300): 1447 - 1451. [Abstract] [Full Text] [PDF]

				D. Corella, K. Tucker, C. Lahoz, O. Coltell, L A. Cupples, P. W. Wilson, E. J Schaefer, and J. M Ordovas Alcohol drinking determines the effect of the APOE locus on LDL-cholesterol concentrations in men: the Framingham Offspring Study Am. J. Clinical Nutrition, April 1, 2001; 73(4): 736 - 745. [Abstract] [Full Text] [PDF]

				A. T Erkkila, E. S Sarkkinen, V. Lindi, S. Lehto, M. Laakso, and M. I. Uusitupa APOE polymorphism and the hypertriglyceridemic effect of dietary sucrose Am. J. Clinical Nutrition, April 1, 2001; 73(4): 746 - 752. [Abstract] [Full Text] [PDF]

				M. F. Newman, D. T. Laskowitz, W. D. White, J. L. Kirchner, H. P. Grocott, M. Stafford-Smith, M. H. Sketch, R. H. Jones, J. G. Reves, and A. M. Saunders Apolipoprotein E Polymorphisms and Age at First Coronary Artery Bypass Graft Anesth. Analg., April 1, 2001; 92(4): 824 - 829. [Abstract] [Full Text] [PDF]

				T. Isbir, B. Agachan, H. Yilmaz, M. Aydin, I. Kara, E. Eker, and D. Eker Apolopoprotein-E gene polymorphism and lipid profiles in Alzheimer's disease American Journal of Alzheimer's Disease and Other Dementias, March 1, 2001; 16(2): 77 - 81. [Abstract] [PDF]

				M. M. HOFFMANN, H. SCHARNAGL, E. PANAGIOTOU, W. T. BANGHARD, H. WIELAND, and W. MÄRZ Diminished LDL Receptor and High Heparin Binding of Apolipoprotein E2 Sendai Associated with Lipoprotein Glomerulopathy J. Am. Soc. Nephrol., March 1, 2001; 12(3): 524 - 530. [Abstract] [Full Text]

				G. Lembo, N. De Luca, C. Battagli, G. Iovino, A. Aretini, M. Musicco, G. Frati, F. Pompeo, C. Vecchione., and B. Trimarco A Common Variant of Endothelial Nitric Oxide Synthase (Glu298Asp) Is an Independent Risk Factor for Carotid Atherosclerosis Stroke, March 1, 2001; 32(3): 735 - 740. [Abstract] [Full Text] [PDF]

				G. B. Frisoni, J. Louhija, C. Geroldi, and M. Trabucchi Longevity and the {{varepsilon}}2 Allele of Apolipoprotein E: The Finnish Centenarians Study J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2001; 56(2): 75M - 78. [Abstract] [Full Text]

				C. M. Ballantyne, J. A. Herd, E. A. Stein, L. L. Ferlic, J. K. Dunn, A. M. Gotto Jr., and A. J. Marian Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1572 - 1578. [Abstract] [Full Text] [PDF]

				J. Dong, M. E. Balestra, Y. M. Newhouse, and K. H. Weisgraber Human apolipoprotein E7: lysine mutations in the carboxy-terminal domain are directly responsible for preferential binding to very low density lipoproteins J. Lipid Res., November 1, 2000; 41(11): 1783 - 1789. [Abstract] [Full Text]

				R. Frikke-Schmidt, B. G. Nordestgaard, B. Agerholm-Larsen, P. Schnohr, and A. Tybjærg-Hansen Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype J. Lipid Res., November 1, 2000; 41(11): 1812 - 1822. [Abstract] [Full Text]