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Thromb Haemost 1999; 82(06): 1709-1717
DOI: 10.1055/s-0037-1614903
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Schattauer GmbH

The Identification of Polymorphisms in the Coding Region of the Apolipoprotein (a) Gene

Association with Earlier Identified Polymorphic Sites and Influence on the Lipoprotein (a) Concentration
Janke Prins
1   From the Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands
,
Frank R. Leus
1   From the Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands
,
Bonno N. Bouma
1   From the Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands
,
Herman J. M. van Rijn
1   From the Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 08 April 1999

Accepted after revision 25 May 1999

Publication Date:
10 December 2017 (online)

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Summary

Lipoprotein (a) [Lp(a)] is a quantitative genetic trait in human plasma and elevated levels represent a major inherited risk factor for the development of atherosclerotic disease. In our search for sequence polymorphisms in the coding region of the apolipoprotein(a) [apo(a)] gene that may affect the Lp(a) concentration, four new polymorphic sites were identified. These include two coinciding polymorphisms with an allele frequency of 38% located at amino acid positions 87 and 101 (Leu87,101 →Val) in the interkringle region of kringle IV (K.IV) type 7 and two polymorphisms located in K.IV type 7 (Arg60 →Ser) and in K.IV type 10 (Tyr2 →Phe) both with estimated allele frequencies of about 1%.

The linkage between the newly identified K.IV type 7 Leu87,101 →Val polymorphism and earlier described polymorphic sites in the non-coding and coding regions of the apo(a) gene, its distribution over the apo(a) isoform sizes and its possible influence on the Lp(a) concentration was analysed in 201 healthy unrelated Caucasians. The earlier described polymorphic sites included in this study were the variable number of a TTTTA pentanucleotide repeat (7-11 PNR) starting at -1231 bp, the -772 bp G/A polymorphism, the +93 bp C/T polymorphism and the +121 bp G/A polymorphism in the non-coding region, and the K.IV type 8 Thr12/Pro polymorphism and the K.IV type 10 Thr66/Met polymorphism in the coding region of the apo(a) gene.

Linkage disequilibria were observed between the polymorphic sites in the 5’ non-coding region and the sites in K.IV type 7 and 8 in the coding region of the apo(a) gene, confirming that the expansion of the variable number of K.IV type 2 repeats results from intrachromosomal recombinational events. The distribution over the apo(a) isoform sizes of the K.IV type 7 Val87,101 subtype was not significantly different from that of the K.IV type 7 Leu87,101 wild-type, suggesting a relative ancient mutational event. No influence of the K.IV type 7 Leu87,101 →Val polymorphism on the Lp(a) level was observed. In fact, of all the polymorphic sites studied, only the +121 A subtype could be associated with an increased, and the K.IV type 8 Pro12 and the 10 PNR subtypes with a reduced, Lp(a) concentration corrected for apo(a) isoform size (p <0.05).

Keywords

Apolipoprotein (a) - lipoprotein (a) - polymorphic sites
 

  • References

  • 1 Dahlen GH. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis 1994; 108: 111-26.
    CrossrefPubMedSearch in Google Scholar
  • 2 Gaubatz JW, Heideman C, Gotto AM, Morrisett JD, Dahlen GH. Human plasma lipoprotein(a). Structural properties. J Biol Chem 1983; 258: 4582-9.
    CrossrefPubMedSearch in Google Scholar
  • 3 Koschinsky ML, Cote GP, Gabel B, Van der Hoek YY. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100. J Biol Chem 1993; 268: 19819-25.
    PubMedSearch in Google Scholar
  • 4 Brunner C, Kraft HG, Utermann G, Muller HJ. Cys4057 of apolipoprotein(a) is essential for lipoprotein(a) assembly. Proc Natl Acad Sci USA 1993; 90: 11643-7.
    CrossrefPubMedSearch in Google Scholar
  • 5 McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-7.
    CrossrefPubMedSearch in Google Scholar
  • 6 Guevara Jr. J, Jan AY, Knapp R, Tulinsky A, Morrisett JD. Comparison of ligand-binding sites of modeled apo(a) kringle-like sequences in human lipoprotein(a). Arterioscler Thromb 1993; 13: 758-70.
    CrossrefPubMedSearch in Google Scholar
  • 7 Hoover Plow JL, Miles LA, Fless GM, Scanu AM, Plow EF. Comparison of the lysine binding functions of lipoprotein(a) and plasminogen. Biochemistry 1993; 32: 13681-7.
    CrossrefPubMedSearch in Google Scholar
  • 8 Huby T, Schroder W, Doucet C, Chapman J, Thillet J. Characterization of the N-terminal and C-terminal domains of human apolipoprotein(a): relevance to fibrin binding. Biochemistry 1995; 34: 7385-93.
    CrossrefPubMedSearch in Google Scholar
  • 9 Pfaffinger D, Mc Lean J, Scanu AM. Amplification of human apo(a) kringle 4-37 from blood lymphocyte DNA. Biochim Biophys Acta 1993; 1225: 107-9.
    CrossrefPubMedSearch in Google Scholar
  • 10 Hajjar KA, Nachman RL. The role of lipoprotein(a) in atherogenesis and thrombosis. Annu Rev Med 1996; 47: 423-42.
    CrossrefPubMedSearch in Google Scholar
  • 11 Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992; 90: 52-60.
    CrossrefPubMedSearch in Google Scholar
  • 12 Kraft HG, Kochl S, Menzel HJ, Sandholzer C, Utermann G. The apolipoprotein (a) gene: a transcribed hypervariable locus controlling plasma lipoprotein (a) concentration. Hum Genet 1992; 90: 220-30.
    PubMedSearch in Google Scholar
  • 13 Kraft HG, Lingenhel A, Köchl S, Hoppichler F, Kronenberg F, Abe A, Mühlberger V, Schönitzer D, Utermann G. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol 1996; 16: 713-9.
    CrossrefPubMedSearch in Google Scholar
  • 14 Leus FR, Leerink CB, Prins J, van Rijn HJM. Influence of apolipoprotein(a) phenotype on lipoprotein(a) quantification: evaluation of three methods. Clin Biochem 1994; 27: 449-55.
    CrossrefPubMedSearch in Google Scholar
  • 15 Cohen JC, Chiesa G, Hobbs HH. Sequence polymorphisms in the apolipoprotein (a) gene. Evidence for dissociation between apolipoprotein(a) size and plasma lipoprotein(a) levels. J Clin Invest 1993; 91: 1630-6.
    CrossrefPubMedSearch in Google Scholar
  • 16 Kraft HG, Lingenhel A, Pang RWC, Delport R, Trommsdorff M, Vermaak H, Janus ED, Utermann G. Frequency distributions of apolipoprotein(a) kringle IV repeat alleles and their effects on lipoprotein(a) levels in Caucasian, Asian, and African populations: The distribution of null alleles is nonrandom. Eur J Hum Genet 1996; 4: 74-87.
    CrossrefPubMedSearch in Google Scholar
  • 17 Frank S, Durovic S, Kostner GM. The assembly of lipoprotein Lp(a). Eur J Clin Invest 1996; 26: 109-14.
    CrossrefPubMedSearch in Google Scholar
  • 18 Mihalich A, Magnaghi P, Sessa L, Trubia M, Acquati F, Taramelli R. Genomic structure and organization of kringles type 3 to 10 of the apolipoprotein(a) gene in 6q26-27. Gene 1997; 196: 1-8.
    CrossrefPubMedSearch in Google Scholar
  • 19 Amemiya H, Arinami T, Kikuchi S, Yamakawa-Kobayashi K, Li L, Fujiwara H, Hiroe M, Marumo F, Hamaguchi H. Apolipoprotein(a) size and pentanucleotide repeat polymorphisms are associated with the degree of atherosclerosis in coronary heart disease. Atherosclerosis 1996; 123: 181-91.
    CrossrefPubMedSearch in Google Scholar
  • 20 Trommsdorff M, Kochl S, Lingenhel A, Kronenberg F, Delport R, Vermaak H, Lemming L, Klausen IC, Faergeman O, Utermann G, Kraft HG. A pentanucleotide repeat polymorphism in the 5’ control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians. J Clin Invest 1995; 96: 150-7.
    CrossrefPubMedSearch in Google Scholar
  • 21 Mooser V, Mancini FP, Bopp S, Petho Schramm A, Guerra R, Boerwinkle E, Muller HJ, Hobbs HH. Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet 1995; 4: 173-81.
    CrossrefPubMedSearch in Google Scholar
  • 22 Puckey LH, Lawn RM, Knight BL. Polymorphisms in the apolipoprotein(a) gene and their relationship to allele size and plasma lipoprotein(a) concentration. Hum Mol Genet 1997; 6: 1099-107.
    CrossrefPubMedSearch in Google Scholar
  • 23 Bopp S, Kochl S, Acquati F, Magnaghi P, Petho Schramm A, Kraft HG, Utermann G, Muller HJ, Taramelli R. Ten allelic apolipoprotein(a) 5’ flanking fragments exhibit comparable promoter activities in HepG2 cells. J Lipid Res 1995; 36: 1721-8.
    PubMedSearch in Google Scholar
  • 24 Ichinose A, Kuriyama M. Detection of polymorphisms in the 5’-flanking region of the gene for apolipoprotein(a). Biochem Biophys Res Commun 1995; 209: 372-8.
    CrossrefPubMedSearch in Google Scholar
  • 25 Suzuki K, Kuriyama M, Saito T, Ichinose A. Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5’-flanking region. J Clin Invest 1997; 99: 1361-6.
    CrossrefPubMedSearch in Google Scholar
  • 26 Zysow BR, Lindahl GE, Wade DP, Knight BL, Lawn RM. C/T polymorphism in the 5’ untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation. Arterioscler Thromb Vasc Biol 1995; 15: 58-64.
    CrossrefPubMedSearch in Google Scholar
  • 27 Fless GM, Furbee Jr. J, Snyder ML, Meredith SC. Ligand-induced conformational change of lipoprotein(a). Biochemistry 1996; 35: 2289-98.
    CrossrefPubMedSearch in Google Scholar
  • 28 Scanu AM, Edelstein C. Kringle-dependent structural and functional polymorphism of apolipoprotein (a). Biochim Biophys Acta 1995; 1256: 1-12.
    CrossrefPubMedSearch in Google Scholar
  • 29 Ernst A, Helmhold M, Brunner C, Petho Schramm A, Armstrong VW, Muller HJ. Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a). J Biol Chem 1995; 270: 6227-34.
    CrossrefPubMedSearch in Google Scholar
  • 30 Van der Hoek YY, Kastelein JJP, Koschinsky ML. Analysis of structure-function relationships in human apolipoprotein(a). Can J Physiol Pharmacol 1994; 72: 304-10.
    CrossrefPubMedSearch in Google Scholar
  • 31 Van der Hoek YY, Wittekoek ME, Beisiegel U, Kastelein JJP, Koschinsky ML. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms. Hum Mol Genet 1993; 2: 361-6.
    CrossrefPubMedSearch in Google Scholar
  • 32 Scanu AM. Structural and functional polymorphism of lipoprotein(a): Biological and clinical implications. Clin Chem 1995; 41: 170-2.
    PubMedSearch in Google Scholar
  • 33 Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 1987; 80: 458-65.
    CrossrefPubMedSearch in Google Scholar
  • 34 Marcovina SM, Hobbs HH, Albers JJ. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature. Clin Chem 1996; 42: 436-9.
    PubMedSearch in Google Scholar
  • 35 Trieu VN, McConathy WJ. A two-step model for lipoprotein(a) formation. J Biol Chem 1995; 270: 15471-4.
    CrossrefPubMedSearch in Google Scholar
  • 36 Kraft HG, Haibach C, Lingenhel A, Brunner C, Trommsdorff M, Kronenberg F, Muller HJ, Utermann G. Sequence polymorphism in kringle IV 37 in linkage disequilibrium with the apolipoprotein (a) size polymorphism. Hum Genet 1995; 95: 275-82.
    PubMedSearch in Google Scholar
  • 37 Scanu AM. Identification of mutations in human apolipoprotein(a) kringle 4-37 from the study of the DNA of peripheral blood lymphocytes: relevance to the role of lipoprotein(a) in atherothrombosis. Am J Cardiol 1995; 75: 58B-61B.
    CrossrefPubMedSearch in Google Scholar
  • 38 Prins J, Leus FR, Van der Hoek YY, Kastelein JJP, Bouma BN, Van Rijn HJM. The identification and significance of a Thr→Pro polymorphism in Kringle IV type 8 of apolipoprotein(a). Thromb Haemost 1997; 77: 949-54.
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Kamboh MI, Ferrell RE, Kottke BA. Expressed hypervariable polymorphism of apolipoprotein (a). Am J Hum Genet 1991; 49: 1063-74.
    PubMedSearch in Google Scholar
  • 40 Terwilliger J, Ott J. Handbook for human genetic linkage. Baltimore: John Hopkins University Press; 1994
    Search in Google Scholar
  • 41 Thompson EA, Deeb S, Walker D, Motulsky AG. The detection of linkage disequilibrium between closely linked markers. Am J Hum Genet 1988; 42: 113-24.
    PubMedSearch in Google Scholar
  • 42 Kraft HG, Windegger M, Menzel HJ, Utermann G. Significant impact of the +93 C/T polymorphism in the apolipoprotein(a) gene on Lp(a) concentrations in Africans but not in Caucasians: confounding effect of linkage disequilibrium. Hum Mol Genet 1998; 7: 257-64.
    CrossrefPubMedSearch in Google Scholar
  • 43 Ichinose A. Characterization of the apolipoprotein(a) gene. Biochem Biophys Res Commun 1995; 209: 365-71.
    CrossrefPubMedSearch in Google Scholar
  • 44 Scanu AM, Pfaffinger D, Lee JC, Hinman J. A single point mutation (Trp72→Arg) in human apo(a) kringle 4-37 associated with a lysine binding defect in Lp(a). Biochim Biophys Acta 1994; 1227: 41-5.
    CrossrefPubMedSearch in Google Scholar
  • 45 Marcovina SM, Albers JJ, Wijsman E, Zhang ZH, Chapman NH, Kennedy H. Differences in Lp(a) concentrations and apo(a) polymorphs between black and white Americans. J Lipid Res 1996; 37: 2569-85.
    PubMedSearch in Google Scholar
  • 46 Wade DP, Clarke JG, Lindahl GE, Liu AC, Zysow BR, Meer K, Schwartz K, Lawn RM. 5’ Control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family. Proc Natl Acad Sci USA 1993; 90: 1369-73.
    CrossrefPubMedSearch in Google Scholar
  • 47 Guevara J, Knapp RD, Honda S, Northup SR, Morrisett JD. A structural assessment of the apo(a) protein of human lipoprotein(a). Proteins 1992; 12: 188-99.
    CrossrefPubMedSearch in Google Scholar
  • 48 Edelstein C, Italia JA, Scanu AM. Polymorphonuclear cells isolated from human peripheral blood cleave lipoprotein(a) and apolipoprotein(a) at multiple interkringle sites via the enzyme elastase. J Biol Chem 1997; 272: 11079-87.
    CrossrefPubMedSearch in Google Scholar
  • 49 Scanu AM, Edelstein C. Learning about the structure and biology of human lipoprotein(a) through dissection by enzymes of the elastase family: facts and speculations. J Lipid Res 1997; 38: 2193-206.
    PubMedSearch in Google Scholar