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Am J Hum Genet. Mar 1985; 37(2): 268–285.
PMCID: PMC1684560

Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.


The structural gene locus for apolipoprotein E (apo E) is polymorphic. Three common alleles (epsilon 2, epsilon 3, epsilon 4) code for three major isoforms in plasma and determine six apo E phenotypes that may be identified by isoelectric focusing on polyacrylamide. To establish what fraction of the inherited variation in a normal plasma lipid and lipoprotein profile is attributable to the segregation of the common alleles at the apo E gene locus, we have estimated the average apo E allelic effects on plasma cholesterol (C), triglycerides, very low-density lipoprotein (VLDL)-C, VLDL-apo B, low-density lipoprotein (LDL)-C, LDL-apo B, and high-density lipoprotein (HDL)-C in a representative sample of normolipidemic individuals from Ottawa, Canada. Data from published studies were also analyzed by the same statistical procedures. As much as 16% of the genetic variance (8.3% of the total variance) for LDL-C could be accounted for by the apo E gene locus. After correction for differences in age, sex, height, and weight, it was found that the epsilon 2 allele lowered and the epsilon 4 allele raised total cholesterol, LDL-C, and LDL-apo B. No other gene has been identified that contributes as much to normal cholesterol variability. Analysis of these data and those of others also indicates that the apo E locus imparts a differential susceptibility to a variety of factors that promote hyperlipidemia. The hypothesis is proposed that the epsilon 2 allele protects against coronary heart disease (CHD) and, hence, gives a reproductive advantage that is balanced by a predisposition to CHD when the epsilon 2 is combined with a second, independent causative factor to give a reproductive disadvantage. A similar mechanism is proposed for the maintenance of the epsilon 4 allele in the population.

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  • Mahley RW, Innerarity TL. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta. 1983 May 24;737(2):197–222. [PubMed]
  • Blue ML, Williams DL, Zucker S, Khan SA, Blum CB. Apolipoprotein E synthesis in human kidney, adrenal gland, and liver. Proc Natl Acad Sci U S A. 1983 Jan;80(1):283–287. [PMC free article] [PubMed]
  • Basu SK, Ho YK, Brown MS, Bilheimer DW, Anderson RG, Goldstein JL. Biochemical and genetic studies of the apoprotein E secreted by mouse macrophages and human monocytes. J Biol Chem. 1982 Aug 25;257(16):9788–9795. [PubMed]
  • Roheim PS, Carey M, Forte T, Vega GL. Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4646–4649. [PMC free article] [PubMed]
  • Innerarity TL, Mahley RW. Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins. Biochemistry. 1978 Apr 18;17(8):1440–1447. [PubMed]
  • Mahley RW, Hui DY, Innerarity TL, Weisgraber KH. Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors. J Clin Invest. 1981 Nov;68(5):1197–1206. [PMC free article] [PubMed]
  • Havel RJ, Chao Y, Windler EE, Kotite L, Guo LS. Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4349–4353. [PMC free article] [PubMed]
  • Mahley RW. Atherogenic hyperlipoproteinemia. The cellular and molecular biology of plasma lipoproteins altered by dietary fat and cholesterol. Med Clin North Am. 1982 Mar;66(2):375–402. [PubMed]
  • Basu SK, Goldstein JL, Brown MS. Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages. Science. 1983 Feb 18;219(4586):871–873. [PubMed]
  • Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 1977 Oct 13;269(5629):604–607. [PubMed]
  • Zannis VI, Breslow JL. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 1981 Feb 17;20(4):1033–1041. [PubMed]
  • Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR, et al. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res. 1982 Aug;23(6):911–914. [PubMed]
  • Utermann G, Steinmetz A, Weber W. Genetic control of human apolipoprotein E polymorphism: comparison of one- and two-dimensional techniques of isoprotein analysis. Hum Genet. 1982;60(4):344–351. [PubMed]
  • Bouthillier D, Sing CF, Davignon J. Apolipoprotein E phenotyping with a single gel method: application to the study of informative matings. J Lipid Res. 1983 Aug;24(8):1060–1069. [PubMed]
  • Weisgraber KH, Rall SC, Jr, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981 Sep 10;256(17):9077–9083. [PubMed]
  • Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, Weber W, Havel RJ, Kotite L, Kane JP, Innerarity TL, et al. Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. J Clin Invest. 1981 Oct;68(4):1075–1085. [PMC free article] [PubMed]
  • Rall SC, Jr, Weisgraber KH, Innerarity TL, Mahley RW. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4696–4700. [PMC free article] [PubMed]
  • Gregg RE, Ghiselli G, Brewer HB., Jr Apolipoprotein EBethesda: a new variant of apolipoprotein E associated with type III hyperlipoproteinemia. J Clin Endocrinol Metab. 1983 Nov;57(5):969–974. [PubMed]
  • Jain RS, Quarfordt SH. The carbohydrate content of apolipoprotein E from human very low density lipoproteins. Life Sci. 1979 Oct 8;25(15):1315–1323. [PubMed]
  • Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ. Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2. J Lipid Res. 1982 Nov;23(8):1224–1235. [PubMed]
  • Wardell MR, Suckling PA, Janus ED. Genetic variation in human apolipoprotein E. J Lipid Res. 1982 Nov;23(8):1174–1182. [PubMed]
  • Menzel HJ, Kladetzky RG, Assmann G. Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983 Jul-Aug;3(4):310–315. [PubMed]
  • Ghiselli G, Gregg RE, Zech LA, Schaefer EJ, Brewer HB., Jr Phenotype study of apolipoprotein E isoforms in hyperlipoproteinaemic patients. Lancet. 1982 Aug 21;2(8295):405–407. [PubMed]
  • Cumming AM, Robertson FW. Polymorphism at the apoprotein-E locus in relation to risk of coronary disease. Clin Genet. 1984 Apr;25(4):310–313. [PubMed]
  • Havel RJ. Familial dysbetalipoproteinemia. New aspects of pathogenesis and diagnosis. Med Clin North Am. 1982 Mar;66(2):441–454. [PubMed]
  • Ghiselli G, Schaefer EJ, Gascon P, Breser HB., Jr Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science. 1981 Dec 11;214(4526):1239–1241. [PubMed]
  • Muller DP, Pavlou C, Whitelaw AG, McLintock D. The effect of pregnancy and two different contraceptive pills on serum lipids and lipoproteins in a woman with a type III hyperlipoproteinaemia pattern. Br J Obstet Gynaecol. 1978 Feb;85(2):127–133. [PubMed]
  • Hazzard WR, Warnick GR, Utermann G, Albers JJ. Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dysbetalipoproteinemia and hyperlipidemia. Metabolism. 1981 Jan;30(1):79–88. [PubMed]
  • Davignon J, Bouthillier D, Dufour R, Lussier-Cacan S. Xanthomes et athérosclérose en présence de lipides plasmatiques normaux. Ann Med Interne (Paris) 1983;134(5):483–491. [PubMed]
  • Ghiselli G, Schaefer EJ, Zech LA, Gregg RE, Brewer HB., Jr Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. J Clin Invest. 1982 Aug;70(2):474–477. [PMC free article] [PubMed]
  • Sing CF, Orr JD. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. IV. Separation of polygene from common environment effects. Am J Hum Genet. 1978 Sep;30(5):491–504. [PMC free article] [PubMed]
  • Moll PP, Powsner R, Sing CF. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. V. Variance components estimated from pedigrees. Ann Hum Genet. 1979 Jan;42(3):343–354. [PubMed]
  • Rao DC, Morton NE, Gulbrandsen CL, Rhoads GG, Kagan A, Yee S. Cultural and biological determinants of lipoprotein concentrations. Ann Hum Genet. 1979 May;42(4):467–477. [PubMed]
  • Hewitt D, Jones GJ, Godin GJ, McComb K, Breckenridge WC, Little JA, Steiner G, Mishkel MA, Baillie JH, Martin RH, et al. Normative standards of plasma cholesterol and triglyceride concentrations in Canadians of working age. Can Med Assoc J. 1977 Nov 5;117(9):1020–1024. [PMC free article] [PubMed]
  • Jones GJ, Hewitt D, Godin GJ, Breckenridge WC, Bird J, Mishkel MA, Steiner G, Little JA. Plasma lipoprotein levels and the prevalence of hyperlipoproteinemia in a Canadian working population. Can Med Assoc J. 1980 Jan 12;122(1):37–46. [PMC free article] [PubMed]
  • Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed]
  • Sampson EJ, Demers LM, Krieg AF. Faster enzymatic procedure for serum triglycerides. Clin Chem. 1975 Dec;21(13):1983–1985. [PubMed]
  • Reardon MF, Poapst ME, Uffelman KD, Steiner G. Improved method for quantitation of B apoprotein in plasma lipoproteins by electroimmunoassay. Clin Chem. 1981 Jun;27(6):892–895. [PubMed]
  • Rosseneu M, Vinaimont N, Vercaemst R, Dekeersgieter W, Belpaire F. Standardization of immunoassays for the quantitation of plasma Apo B protein. Anal Biochem. 1981 Sep 1;116(1):204–210. [PubMed]
  • Connor SL, Connor WE, Sexton G, Calvin L, Bacon S. The effects of age, body wight and family relationships on plasma lipoproteins and lipids in men, women and children of randomly selected families. Circulation. 1982 Jun;65(7):1290–1298. [PubMed]
  • Sing CF, Orr JD. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. III. Identification of genetic effects using 12 polymorphic genetic blood marker systems. Am J Hum Genet. 1976 Sep;28(5):453–464. [PMC free article] [PubMed]
  • Sing CF, Chamberlain MA, Block WD, Feiler S. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. I. Analysis of the frequency distribution for evidence of a genetic polymorphism. Am J Hum Genet. 1975 May;27(3):333–347. [PMC free article] [PubMed]
  • Nevo E. Genetic variation in natural populations: patterns and theory. Theor Popul Biol. 1978 Feb;13(1):121–177. [PubMed]
  • Rosenblum BB, Neel JV, Hanash SM. Two-dimensional electrophoresis of plasma polypeptides reveals "high" heterozygosity indices. Proc Natl Acad Sci U S A. 1983 Aug;80(16):5002–5006. [PMC free article] [PubMed]
  • Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med. 1979 Jan;90(1):85–91. [PubMed]
  • Rall SC, Jr, Weisgraber KH, Innerarity TL, Mahley RW. Identical structural and receptor binding defects in apolipoprotein E2 in hypo-, normo-, and hypercholesterolemic dysbetalipoproteinemia. J Clin Invest. 1983 Apr;71(4):1023–1031. [PMC free article] [PubMed]
  • Utermann G, Pruin N, Steinmetz A. Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. Clin Genet. 1979 Jan;15(1):63–72. [PubMed]

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