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Association of apolipoprotein B gene variants with plasma apoB and low density lipoprotein (LDL) cholesterol levels

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Summary

The contribution of the variants of the apolipoprotein (apo) B locus to the total variance in plasma apoB and cholesterol levels was examined in four independent populations, two that were composed of normal controls (n = 77 and 85) and two with coronary heart disease (n = 115 and 159). A correlation between genotype at the apoB-XbaI locus and apoB levels was observed. The effects of the (+; presence of restriction site) and (-) alleles were to increase or decrease the apoB and cholesterol levels by approximately 3.5 mg/dl, respectively. None of the 274 individuals in the coronary heart disease (CHD) groups was found to be a carrier of the apoB allele Arg3500→Gln, previously shown to be associated with an apoB protein defective in binding to the low density lipoprotein receptor (LDL-R). No DNA sequence variants were found in the region encoding amino acid residues 3129–3532 within the putative LDL-R binding domain among 35 individuals with apoB levels above the 94th percentile (141 mg/dl).

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References

  • Aburatani H, Murase T, Takaku F, Itoh H, Matsumoto A, Itakura H (1987) Apolipoprotein B-gene polymorphism and myocardial infarction. N Engl J Med 317:52–56

    Google Scholar 

  • Albers JJ, Cabana VG, Hazzard WR (1975) Immunoassay of human plasma apolipoprotein B. Metabolism 24:1339–1351

    CAS  PubMed  Google Scholar 

  • Alto-Setala K, Tikkanen MJ, Taskinen M-R, Nieminen M, Holmberg P, Kontula K (1988) XbaI and c/g polymorphisms of the apolipoprotein B gene locus are associated with serum cholesterol and LDL-cholesterol levels in Finland. Atherosclerosis 74:65–74

    Google Scholar 

  • Avogaro P, Bon GB, Cazzolato G, Quinci GB, Bellussi F (1978) Plasma levels of apolipoprotein AI and apoprotein B in human atherosclerosis. Artery 4:385–394

    Google Scholar 

  • Berg K (1983) Genetics of coronary heart disease. In: Steinberg AG, Bearn AR, Motulsky AG, Childs B (eds) Progress in medical genetics. Saunders, Philadelphia, pp 35–90

    Google Scholar 

  • Berg K (1986) DNA polymorphism at the apolipoprotein B locus is associated with lipoprotein level. Clin Genet 301:515–520

    Google Scholar 

  • Blackhart BD, Ludwig EM, Pierotti R, Caiati L, Onasch MA, Wallis SC, Powell L, Pease R, Knott TJ, Chu M-L, Mahley RW, Scott J, McCarthy BJ, Levy-Wilson B (1986) Structure of the human apolipoprotein b gene. J Biol Chem 261:15364–15367

    CAS  PubMed  Google Scholar 

  • Boerwinkle E, Sing CF (1986) Bias of the contribution of singlelocus effects to the variance of a quantitative trait. Am J Hum Genet 39:137–144

    CAS  PubMed  Google Scholar 

  • Brunzell JD, Sniderman AD, Albers JJ, Kwiterovitch PD Jr (1984) Apoproteins B and A-I and coronary artery disease in humans. Arteriosclerosis 4:79–83

    CAS  PubMed  Google Scholar 

  • Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, White R (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–201

    Article  CAS  PubMed  Google Scholar 

  • Cooper DN, Clayton JF (1988) DNA polymorphism and the study of disease associations. Hum Genet 78:299–312

    CAS  PubMed  Google Scholar 

  • Dahlen GH, Gayton HR, Attar M, Farmer JA, Kautz JA, Gotto AM (1986) Association of levels of LP(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation 74:758–765

    CAS  PubMed  Google Scholar 

  • Deeb SS, Failor A, Brown BG, Brunzell JD, Albers JJ, Motulsky AJ (1986a) Molecular genetics of apolipoproteins and coronary heart disease. Cold Spring Harb Symp Quant Biol 51:403–409

    CAS  PubMed  Google Scholar 

  • Deeb SS, Disteche C, Motulsky AG, Lebo RV, Kan YW (1986b) Chromosomal localization of the human apolipoprotein B gene and detection of homologous RNA in monkey intestine. Proc Natl Acad Sci USA 83:419–422

    CAS  PubMed  Google Scholar 

  • Demant T, Houlston RS, Caslake MJ, Series J, Shephard J, Packard CJ, Humphries SE (1988) Catabolic rate of low density lipoprotein is influenced by variation in the apolipoprotein B gene. J Clin Invest 82:797–802

    CAS  PubMed  Google Scholar 

  • DHHS (1980) Lipid research clinics population studies data book: the prevalence study. (NIH publication number 80–1527, vol 1) Department of Health and Human Services, Bethesda, Md, pp28–81

    Google Scholar 

  • Fager G, Wiklund O, Olafsson SO (1981) Multivariate analysis of serum apolipoproteins and risk factors in relation to acute myocardial infarction. Arteriosclerosis 1:273–279

    CAS  PubMed  Google Scholar 

  • Falconer DS (1981) Introduction to quantitative genetics, 2nd edn. Longman, NewYork

    Google Scholar 

  • Ferns GAA, Dalton DJ (1986) Frequency of XbaI polymorphism in myocardial infarct survivors. Lancet 11:572

    Google Scholar 

  • Friedl W, Ludwig EH, Paulweber B, Sandhofer F, McCarthy BJ (1990) Hypervariability in a minisatellite 3′ of the apolipoprotein B gene in patients with coronary heart disease compared with normal controls. J Lipid Res 31:659–665

    CAS  PubMed  Google Scholar 

  • Frossard PM, Funke H, Coleman RT, Assman G (1986) Genetic markers for coronary atherosclerosis in the human apolipoprotein AI-CIII-AIV gene complex. Am J Hum Genet 39 [Suppl]:589

    Google Scholar 

  • Gavish D, Brinton EA, Breslow JL (1989) Heritable allele-specific differences in amounts of apoB and low-density lipoproteins in plasma. Science 244:72–75

    CAS  PubMed  Google Scholar 

  • Hegele RA, Breslow JL (1987) Apoprotein genetic variation in the assessment of atherosclerosis susceptibility. Genet Epidemiol 4:163–184

    Article  CAS  PubMed  Google Scholar 

  • Hegele RA, Huang L-S, Herbert PN, Blum CB, Buring JE, Hen-nekens CH, Breslow JL (1986) Apolipoprotein B-gene polymorphisms associated with myocardial infarction. N Engl J Med 515:1509–1515

    Google Scholar 

  • Henderson HE, Landon SV, Michie J, Berger GMB (1987) Association of DNA polymorphism in the apolipoprotein C-III gene with diverse hyperlipidemic phenotypes. Hum Genet 75:62–65

    CAS  PubMed  Google Scholar 

  • Humphries SE (1988) DNA polymorphisms of the apolipoprotein genes — their use in the investigation of the genetic component of hyperlipidemia and atherosclerosis. Atherosclerosis 72:89–108

    Article  CAS  PubMed  Google Scholar 

  • Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, Grundy SM (1987) Familial defective apolipo-protein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84:6919–6923

    CAS  PubMed  Google Scholar 

  • Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, Grundy SM, Friedl W, Davignon J, McCarthy BJ (1990) Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res 31:1337–1349

    CAS  PubMed  Google Scholar 

  • Kessling AM, Horsthemke B, Humphries SE (1985) A study of DNA polymorphisms around the human apolipoprotein A-I gene in hyperlipidemic and normal individuals. Clin Genet 28:296–306

    CAS  PubMed  Google Scholar 

  • Knoff TT, Pease RJ, Powel LM, Wallis SC, Rall SC JR, Innerarity TL, Blackhart B, Taylor WH, Marcel Y, Milne R, Johnson D, Fuller M, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J (1986) Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323:734–738

    Google Scholar 

  • Lipid Research Clinic (1974) Manual of laboratory operations. US Department of Health, Education and Welfare, Washington, DC

    Google Scholar 

  • Lusis AJ (1988) Genetic factors affecting blood lipoproteins: the candidate gene approach. J Lipid Res 29:397–429

    CAS  PubMed  Google Scholar 

  • Maciejko JJ, Holmes DR, Kottle RA, Zinsmeisker AR, Dinh DM, Mao SJT (1983) Apolipoprotein A-I as a marker of angiographically assessed coronary artery disease. N Engl J Med 309:385–389

    CAS  PubMed  Google Scholar 

  • Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 382–401

    Google Scholar 

  • Miller GJ, Miller NE (1975) Plasma high density lipoprotein concentrations and development of ischemic heart diseases. Lancet I:16–19

    Google Scholar 

  • Milne R, Theolis R Jr, Maurice R, Pease RJ, Weech PK, Rassart E, Fruchart J-C, Scott J, Marcel YL (1989) The use of monoclonal antibodies to localize the low density lipoprotein receptor-binding domain of apolipoprotein B. J Biol Chem 264:19754–19760

    CAS  PubMed  Google Scholar 

  • Neter J, Wasserman W, Kutner MH (1986) Applied linear statistical models, 2nd edn. Irwin, Homewood, Ill, pp 618–622, 950–952

    Google Scholar 

  • Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879

    Article  CAS  PubMed  Google Scholar 

  • Price WH, Kitchin AH, Burgon PRS, Morris SW, Wenham PR, Donald PM (1989) DNA restriction fragment length polymorphisms as markers of familial coronary heart disease. Lancet I:1407–1411

    Google Scholar 

  • Rajput-Williams J, Wallis SC, Yarnell J, Bell GI, Knott TJ, Sweetnam P, Cox N, Miller NE, Scott J (1988) Variation of apolipoprotein-B gene is associated with obesity, high blood cholesterol levels and increased risk of coronary heart disease. Lancet II:1442–1446

    Google Scholar 

  • Rees A, Stocks J, Shoulders CC, Galton DJ, Baralle FE (1983) DNA polymorphism adjacent to human apolipoprotein A-I gene: relation to hypertriglyceridemia. Lancet II:444–446

    Google Scholar 

  • Rees A, Stocks J, Williams LG, Caplin JL, Jowett NI, Camm AJ, Galton DJ (1985) DNA polymorphisms in the apolipoprotein C-III and insulin genes and atherosclerosis. Atherosclerosis 58:269–275

    Article  CAS  PubMed  Google Scholar 

  • Rees A, Stocks J, Paul H, Galton D (1986) Haplotypes indentified by DNA polymorphisms at the apolipoprotein A-I and C-III loci and hypertriglyceridemia: a study in Japanese population. Hum Genet 72:168–171

    Article  CAS  PubMed  Google Scholar 

  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491

    CAS  PubMed  Google Scholar 

  • Series J, Cameron I, Caslake M, Gaffrey D, Packard CJ, Shepard J (1989) The XbaI polymorphism of the apolipoprotein B gene influences the degradation of low density lipoprotein in vitro. Biochim Biophys Acta 1003:183–188

    CAS  PubMed  Google Scholar 

  • Soria LF, Ludwig EH, Clark HRG, Vega GL, Grundy SM, McCarthy BJ (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591

    CAS  PubMed  Google Scholar 

  • Talmud PJ, Barni N, Kessling AM, Carlsson P, Darnfors C, Bjursell G, Galton D, Wynn V, Kirk H, Hayden MR, Humphries SE (1987) Apolipoprotein gene variants are involved in the determination of serum cholesterol levels: a study in normo and hyperlipidaemic individuals. Atherosclerosis 67:81–89

    Article  CAS  PubMed  Google Scholar 

  • Thompson EA, Deeb S, Walker D, Motulsky AG (1988) The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet 42:113–124

    CAS  PubMed  Google Scholar 

  • Wojciechowski AP, Farral M, Cullen P, Wilson TME, Bayliss JD, Farren B, Griffin BA, Caslake MJ, Packard CJ, Shepherd J, Thakker R, Scott J (1991) Familial combined hyperlipidemia linked to apolipoprotein AI-CIII-AIV gene clusters on chromosome 11q23–q24. Nature 349:161–164

    Article  CAS  PubMed  Google Scholar 

  • Yang C-Y, Chen S-H, Gianturco SH, Bradley WA, Sparrow JT, Tanimura M, Li W-H, Spanow DA, Deloof H, Rosseneau M, Lee F-S, Gu Z-W, Gotto AM Jr, Chan L (1986) Sequence, structure, receptor binding domains and internal repeats of human apolipoprotein B-100. Nature 323:738–742

    Article  CAS  PubMed  Google Scholar 

  • Young SG, Bertics SJ, Scott TM, Dubois BW, Teltz WF, Curtis LK, Witzum JL (1987) Apolipoprotein B allotypes MB 191 and MB 192 in subjects with coronary artery disease and hypercholeslerolemia. Arteriosclerosis 7:61–65

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, University of Washington, 98195, Seattle, WA, USA

    Samir S. Deeb, R. Alan Failor, B. Greg Brown, John D. Brunzell, John J. Albers, Arno G. Motulsky & Ellen Wijsman

  2. Department of Genetics, University of Washington, 98195, Seattle, WA, USA

    Samir S. Deeb & Arno G. Motulsky

  3. Center for Inherited Diseases, University of Washington, 98195, Seattle, WA, USA

    Samir S. Deeb & Arno G. Motulsky

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  1. Samir S. Deeb
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  2. R. Alan Failor
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  4. John D. Brunzell
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  7. Ellen Wijsman
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Deeb, S.S., Failor, R.A., Brown, B.G. et al. Association of apolipoprotein B gene variants with plasma apoB and low density lipoprotein (LDL) cholesterol levels. Hum Genet 88, 463–470 (1992). https://doi.org/10.1007/BF00215683

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  • DOI: https://doi.org/10.1007/BF00215683

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