Summary
By isoelectric focusing of delipidated sera followed by immunoblotting we studied the apolipoprotein (apo) E polymorphism in 2018 randomly selected 35-years-old males from three different areas in the Netherlands. Comparison of the APOE allele (E*2, E*3, and E*4) frequencies estimated in this study with those reported for several other population samples showed that there are marked differences between the Dutch population and the populations of Japan, New Zealand, Finland, and the United States. These differences in APOE allele frequencies appeared to be mainly due to differences in frequencies of the E*2 allele (decreased in Japan and Finland; increased in New Zealand) and the E*4 allele (increased in Finland; decreased in Japan and the United States). No difference in APOE allele frequencies was found between the Dutch population and the populations of West Germany and Scotland. Measurements of plasma cholesterol and apo B and E concentrations showed that the E*4 allele is associated with elevated plasma cholesterol and apo B levels and with decreased apo E concentrations, whereas the opposite is true for the E*2 allele. In the Dutch population, the sum of average allelic effects of the common APOE alleles on plasma cholesterol and apo B levels is 6.8% and 14.2%, respectively, of the total population mean. The total average allelic effect on plasma apo E concentrations was more pronounced (50.1%), suggesting that the APOE alleles primarily affect apo E concentrations rather than plasma cholesterol and apo B levels. This hypothesis is sustained by the observation that for plasma apo E levels the genetic variance associated with the APOE gene locus contributed about 18% to the total phenotypic variance. For plasma cholesterol and apo B this contribution was only 1.4% and 2.3% and is relatively low as compared with that reported for other population samples.
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References
Boerwinkle E, Utermann G (1988) Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Am J Hum Genet 42:104–112
Boerwinkle E, Visvikis S, Welsh D, Steinmetz J, Hanash SM, Sing CF (1987) The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, beta-lipoprotein, and triglycerides in a sample of unrelated individuals. Am J Med Genet 27:567–582
Bury J, Vercaemst R, Rosseneu M, Belpaire F (1986) Apolipoprotein E quantified by enzyme-linked immunosorbent assay. Clin Chem 32:265–270
Cumming AM, Robertson FW (1984) Polymorphism at the apoprotein-E locus in relation to risk of coronary disease. Clin Genet 25: 310–313
Ehnholm C, Lukka M, Kuusi T, Nikkilä E, Utermann G (1986) Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res 27:227–235
Eto M, Watanabe K, Ishii K (1986a) A racial difference in apolipoprotein E allele frequencies between the Japanese and Caucasian populations. Clin Genet 30:422–427
Eto M, Watanabe K, Ishii K (1986b) Reciprocal effects of apolipoprotein E alleles (ɛ2 and ɛ4) on plasma lipid levels in normolipidemic subjects. Clin Genet 29:477–484
Ghiselli G, Gregg RE, Brewer HB (1984) Apolipoprotein E-Bethesda. Isolation and partial characterization of a variant of human apolipoprotein E isolated from very low density lipoproteins. Biochim Biophys Acta 794:333–339
Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest 78:815–821
Havekes L, Wit E de, Gevers Leuven J, Klasen E, Utermann G, Weber W, Beisiegel U (1986) Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia. Hum Genet 73:157–163
Havekes L, Knijff P de, Beisiegel U, Havinga J, Smit M, Klasen E (1987) A rapid micro-method for apolipoprotein E phenotyping directly in serum. J Lipid Res 28:445–463
Havel RJ, Kotite L, Kane JP, Tun P, Bersot T (1983) A typical dysbeta-lipo-proteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest 72:379–387
Innerarity TL, Weisgraber KH, Arnold KS, Rall SC, Mahley RW (1984) Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site confirmation. J Biol Chem 259:7261–7267
Menzel HJ, Kladetzky RG, Assmann G (1983) Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis 3: 310–315
Ordovas JM, Litwack-Klein L, Wilson PWF, Schaefer MM, Schaeffer EJ (1987) Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res 28:371–380
Rall SC, Weisgraber KH, Innerarity TL, Mahley RW (1982) Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci USA 79:4696–4700
Rall SC, Weisgraber KH, Innerarity TL, Bersot TP, Mahley RW (1983) Identification of a new structural variant of a human apolipoprotein E, E2(Lys146→Gln), in a type III hyperlipoproteinemic subject with the E3/E2 phenotype. J Clin Invest72:1288–1297
Robertson FW, Cumming AM (1985) Effects of apoprotein E polymorphism on serum lipoprotein concentration. Arteriosclerosis 5:283–292
Rossenau M, Vinaimont N, Vercaemst R, Dekeersgieter W, Belpaire F (1981) Standardization of immunoassays for the quantitation of plasma apo B protein. Anal Biochem 116:204–210
Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, Weber W, Havel RJ, Kotite L, Kane JP, Innerarity TL, Mahley RW (1981) 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 68:1075–1085
Sherrill BC, Innerarity TL, Mahley RW (1980) Rapid hepatic clearance of the canine lipoproteins containing only the E apoprotein by a high affinity receptor. J Biol Chem 255:1804–1807
Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37:268–285
Utermann G (1985) Morgagni lecture. Genetic polymorphism of apolipoprotein E-impact on plasma lipoprotein metabolism. In: Crepaldi G, Tiengo A, Baggio G (eds) Diabetes, obesity and hyperlipidemias, vol 3. Elsevier, Amsterdam New York, pp 1–28
Utermann G (1987) Apolipoprotein E polymorphism in health and disease. Am Heart J 113:433–440
Utermann G, Pruin N, Steinmetz A (1979) Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. Clin Genet 15:63–72
Utermann G, Steinmetz A, Weber W (1982) Genetic control of human apolipoprotein E polymorphism: comparison of one- and two-dimensional techniques of isoprotein analysis. Hum Genet 60:344–351
Utermann G, Kindermann I, Kaffarnik H, Stenmetz A (1984a) Apolipoprotein E phenotypes and hyperlipidemia. Hum Genet 65: 232–236
Utermann G, Hardewig A, Zimmer F (1984b) Apolipoprotein E phenotype in patients with myocardial infarction. Hum Genet 65: 237–241
Wardell MR, Suckling PA, Janus ED (1982) Genetic variation in human apolipoprotein E. J Lipid Res 23:1174–1182
Weisgraber KH, Innerarity TL, Mahley RW (1982) Abnormal lipoprotein receptor binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 257: 2518–2521
Yamamura Y, Yamamoto A, Hiramori K, Nambu S (1984a) A new isoform of apolipoprotein E-apoE5-associated with hyperlipidemia and atherosclerosis. Artherosclerosis 50:159–172
Yamamura T, Yamamoto A, Sumiyoshi T, Hiramori K, Nishioeda Y, Nambu S (1984b) New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest 74:1229–1237
Zannis VI, Breslow JL (1981) Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry 20: 1033–1041
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Smit, M., de Knijff, P., Rosseneu, M. et al. Apolipoprotein E polymorphism in the Netherlands and its effect on plasma lipid and apolipoprotein levels. Hum Genet 80, 287–292 (1988). https://doi.org/10.1007/BF01790099
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DOI: https://doi.org/10.1007/BF01790099