Summary
We report a common DNA polymorphism of the apolipoprotein E (apo E) gene detected with the enzyme HpaI. In an individual who is heterozygous for the polymorphism, two hybridising fragments of DNA, one of 50 kb (the H1 allele) and one of 20 kb (the H2 allele) are detected. In 54 controls the frequency of the rare allele is 0.38 (PIC value 0.36). We have also studied the frequency of the polymorphism in normolipidaemic and hyperlipidaemic individuals whose apo E protein typing is known. In 39 individuals with type III hyperlipidaemia and the apo E phenotype E2E2, the frequency of the H2 allele is 0.97. In contrast, the frequency of the H2 allele in normolipidaemic individuals with the E2E2 phenotype is closer to that found in the general population. Possible explanations for this are discussed.
Similar content being viewed by others
References
Brown MS, Goldstein H, Fredrickson DS (1983) Familial hyperlipoproteinemia (dysbetalipoproteinemia). In: Stanbury JB, Wijngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (eds) The metabolic basis of inherited disease, 5th edn. McGraw-Hill, New York, pp 655–671
Botstein D, White RL, Skolnick M, Davis RW (1980) Construction of a genetic linkage map using restriction fragment length polymorphisms. Am J Hum Genet 32:314–331
Bruns GAP, Karathanasis SK, Breslow JL (1984) Human apolipoprotein A-1-C-III gene comples is located on chromosome 11. Arteriosclerosis 4:97–102
Das HK, McPherson J, Bruns GAP, Karathanasis SK, Breslow JL (1985) Isolation, characterization and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260:6240–6247
Davison PJ, Norton P, Wallis SC, Gill L, Cook M, Williamson R, Humphries SE (1986) There are two gene sequences for human apolipoprotein CI (apo CI) on chromosome 19, one of which is 4kb from the apo E gene. Biochem Biophys Res Commun 136: 876–884
Donald JA, Wallis SC, Kessling A, Tippett P, Robson EB, Ball S, Davies KE, Scambler P, Berg K, Heiberg A, Williamson R, Humphries SE (1985) Linkage relationships of the gene for apolipoprotein CII with loci on chromosome 19. Hum Genet 69:39–43
Feinberg AP, Vogelstein B (1984) Addendum “A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity”. Anal Biochem 137:266–267
Havekes LM, de Knijff P, Beisiegel U, Havinga J, Smit M, Klasen EC (1986) A rapid micro-method for apolipoprotein E phenotyping directly in serum. J Lipid Res (in press)
Hazzard WR, Russell Warnick G, Utermann G, Albers JJ (1981) Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dysbetalipoproteinemia and hyperlipidemia. Metabolism 30:79–88
Hofker MH, Wapenaar MC, Goor N, Bakker E, van Ommen G-JB, Pearson PL (1985) Isolation of probes detecting restriction fragment length polymorphisms from X chromosome-specific libraries: potential use for diagnosis of Duchenne muscular dystrophy. Hum Genet 70:148–156
Humphries SE, Jowett NI, Williams L, Rees A, Vella M, Kessling A, Myklebost O, Lydon A, Seed M, Galton DH, Williamson R (1983) A DNA polymorphism adjacent to the human apo CII gene. Mol Biol Med 1:463–471
Humphries SE, Borresen AL, Gill L, Cumming AM, Robertson FW, Stalenhoef AFH, Williamson R, Berg K (1984) The gene for apolipoprotein CII is closely linked to the gene for apolipoprotein E. Clin Genet 26:389–396
Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachter SS, Miller OJ, Breg WR, Jones W Jr, Rary JM (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Nalt Acad Sci USA 74:1245–1249
Mahley RW, Innerarity TL (1983) Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta 737:197–222
Myklebost O, Rogne S, Olaisen B, Gedde-Dahl T Jr, Prydz H (1984) The locus for apolipoprotein CII is closely linked to the apolipoprotein E locus on chromosome 19 in man. Hum Genet 67:309–312
Myklebost O, Rogne S (1986) The gene for human apolipoprotein CI is located 4.3 kilobases away from the apolipoprotein E gene on chromosome 19. Hum Genet 73:286–289
Olaisen B, Teisberg P, Gedde-Dahl T Jr (1982) The locus for apoliporotein (apoE) is linked to the complement component 3 (C3) locus on chromosome 19 in man. Hum Genet 62:233–236
Paik Young-Ki, Chang DJ, Reardon CA, Davies GE, Mahley RW, Taylor JM (1985) Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci USA 82:3445–3449
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
Shaw DJ, Meredith AL, Sarfarazi M, Huson SM, Brook JD, Myklebost O, Harper PS (1985) The apolipoprotein CII gene: subchromosomal localisation and linkage to the myotonic dystrophy locus. Hum Genet 70:271–273
Sing CF, Davignon J (1985) Role of apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37:268–285
Tata F, Henry I, Markham AF, Wallis SC, Weil D, Grzeschik KH, Junien C, Williamson R, Humphries S (1985) Isolation and characterisation of a cDNA clone for human apolipoprotein CI and assignment of the gene to chromosome 19. Hum Genet 69: 345–349
Utermann G, Vogelberg KH, Steinmetz A, Schoenborn W, Pruin N, Jaeschke M, Hees M, Canzler H (1979a) Polymorphism of apolipoprotein E. II. Genetics of hyperlipoproteinemia type III. Clin Genet 15:37–62
Utermann G, Pruin N, Steinmetz A (1979b) 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, Kindermann I, Kaffarink H, Stenmetz A (1984) Apolipoprotein E phenotypes and hyperlipidaemia. Hum Genet 65: 232–236
Van Ommen GJB, Arnberg AC, Baas F, Brocas H, Sterk A, Tegelaers WHH, Vassart G, de Vijlder JJM (1983) The human thyroglobulin gene contains two 15–17 kb introns near its 3′-end. Nucleic Acids Res 11:2273–2285
Wallis SC, Rogne S, Gill L, Markham A, Edge M, Woods D, Williamson R, Humphries SE (1983) The isolation of cDNA clones for human apolipoprotein E and the detection of apoE RNA in hepatic and extra-hepatic tissues. EMBO J 2:2369–2373
Warnick GR, Mayfield C, Albers JJ, Hazzard WR (1979) Gel isoelectric focussing method for specific diagnosis of familial hyperlipoproteinemia type 3. Clin Chem 25:279–284
Weisgraber KH, Rall SC, Mahley RW (1981) Human E apolipoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the Apo-E isoforms. J Biol Chem 256:9077–9083
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Klasen, E.C., Talmud, P.J., Havekes, L. et al. A common restriction fragment length polymorphism of the human apolipoprotein E gene and its relationship to type III hyperlipidaemia. Hum Genet 75, 244–247 (1987). https://doi.org/10.1007/BF00281067
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00281067