Genetic architecture and evolution of the lipoprotein(a) trait

Current Opinion in Lipidology

Volumn 10, Issue 2, 1999, Pages 133-141

  Utermann, Gerd ^a  

^a Inst for Med Biol and Hum Genet   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

DNA; LIPOPROTEIN A;

ASIAN; CAUCASIAN; DNA POLYMORPHISM; DNA SEQUENCE; EXON; GENE LINKAGE DISEQUILIBRIUM; HUMAN; NEGRO; PRIORITY JOURNAL; RACE DIFFERENCE; REVIEW; START CODON;

APOLIPOPROTEINS A; EVOLUTION, MOLECULAR; HUMANS; LIPOPROTEIN(A); POLYMORPHISM, GENETIC; VARIATION (GENETICS);

ERINACEIDAE; MAMMALIA; PRIMATES;

EID: 0032892174     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-199904000-00007     Document Type: Review

References (51)

1. Utermann G. Lipoprotein(a). In The metabolic and molecular bases of inherited disease Scriver ChR, Beaudet AL, Sly WS, Valle D (editors). New York: McGraw Hill Ino 1995; pp.1887-1912.
2. McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, Fless GM, Scanu AM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 300:132-137
3. Kraft HG, Köchl S, Menzel HJ, Sandholzer C, Utermann G. The apolipoprotein(a) gene a transcribed hypervariable locus controlling plasma lipoprotein(a) concentration. Hum Genet 1992; 90:220-230.
4. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, et al. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations J Clin Invest 1992; 90:52-60.
5. DeMeester CA, Bu X, Gray RJ, Lusis AJ, Rotter JI Genetic variation in lipoprotein(a) levels in families enriched for coronary artery disease is determined almost entirely by the apolipoprotein(a) gene locus. Am J Hum Genet 1995; 56:287-293
6. Mooser V, Scheer D, Marcovina SM, Wang J, Guerra R, Cohen J, Hobbs HH. The apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet 1997, 61:402-417
7. Scholz M, Kraft HG, Lingenhel A, Delport R, Vorster EH, Bickeboller H. Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians. Eur J Hum Genet 1998; 7:147-156. These two studies have dissected the contribution of genetic and non-genetic factors and the contribution of the apo(a) locus to the variance in Lp(a) concentrations in Africans and African Americans using sib-pair linkage and midparent-offspring regression analysis There are differences in details between the studies (e.g. magnitudes of effects) which may be explained by the different samples. Importantly however both studies find evidence for a transacting factor(s) in Africans.
8. Van der Hoek YY, Lingenhel A, Kraft HG, Defesche JC, Kastelein JJP, Utermann G. Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with Familial Defective ApoB. J Clin Invest 1997; 99:2269-2273
9. Lingenhel A, Kraft HG, Kotze M, Peeters AV, Kronenberg F, Kruse R, Utermann G. Concentrations of the atherogenic Lp(a) are elevated in FH Eur J Hum Genet 1998; 6 50-60. The conflicting issue whether or not Lp(a) levels are elevated in familial hypercholesterolemia (FH) and familial defective apoB (FDB) has been addressed in these two studies using sib-pair data. Both studies find a significant effect on Lp(a)
10. Frazer KA, Marla G, Zhang JL, Rubin EM. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice Nature Genet 1995; 9:424-431.
11. Kronenberg F, Utermann G, Dieplinger H. Lipoprotein(a) in renal disease Am J Kidney Dis 1996, 27:1-25.
12. Utermann G. The mysteries of lipoprorein(a). Science 1989;246:904-910.
13. Kraft HG, Lingenhel A, Pang RWC, Delport R, Trommsdorff M, Vermaak H, et al. 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 non-random. Eur J Hum Genet 1996; 4:74-87.
14. Marcovina SM, Zhang ZH, Gaur VP, Albers JJ Identification of 34 apolipoprotein(a) isoforms: differential expression of apolipoprotein(a) alleles between American blacks and whites. Biochem Biophys Res Commun 1993; 191.1192-1196
15. Gaw A, Boerwinkle E, Cohen JC, Hobbs HH Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common 'null' allele at the apo(a) locus J Clin Invest 1994; 93:2526-2534.
16. Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Csaszar A, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet 1991, 86:607-614.
17. Ali S, Bunker CH, Aston CE, Ukoli FA, Kamboh MI. Apolipoprotein A kringle 4 polymorphism and serum lipoprotein(a) concentrations in African blacks. Hum Biol 1998, 70:477-490. A very large study confirming the high Lp(a) in Africans and the weaker contribution of apo(a) isoform variation to the traits variability.
18. Utermann G, Wenzel HJ, Kraft HG, Duba HC, Kemmler HG, et al. Lp(a) glycoprotein phenotypes Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 1987, 80:458-465.
19. Gaubatz JW, Ghanem KI, Guevara J, Jr, Nava ML, Patsch W, Morrisett JD. Polymorphic forms of human apolipoprotein[a]: Inheritance and relationship of their molecular weights to plasma levels of lipoprotein[a]. J Lipid Res 1990; 31:603-613
20. Kamboh MI, Ferrell RE, Kottke BA Expressed hypervariable polymorphism of apolipoprotein(a). Am J Hum Genet 1991; 49:1063-1074.
21. Lackner C, Boerwinkle E, Leffert CC, Rahmig T, Hobbs HH. Molecular basis of apolipoprotein(a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis J Clin Invest 1991; 87:2153-2161.
22. Lackner C, Cohen JC, Hobbs HH. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet 1993; 2:933-940.
23. Haibach C, Kraft HG, Kochl S, Abe A, Utermann G. The number of kringle IV repeats 3-10 is invariable in the human apo(a) gene. Gene 1998; 208:253-258. Direct demonstration by PFGE/Southern blotting that the kringle IV-3 to kringle IV-10 region in the human apo(a) gene does not contain common allelic variation in repeat number.
24. 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; 91:1630-1636
25. Perombelon YFN, Soutar AK, Knight BL. Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles. J Clin Invest 1994, 93:1481-1492
26. Gaw A, Brown EA, Ford I. Impact of apo(a) length polymorphism and the control of plasma Lp(a) concentrations: evidence for a threshold effect. Arterioscler Thromb Vase Biol 1998; 18:1870-1876. Study of the relation between protein-isoforms and Lp(a) levels in a large cohort of hypercholesterolemic Scottish men with very high average Lp(a). The authors conclude that the impact of the size polymorphism has been overestimated in previous studies but there may be objections to this conclusion.
27. Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boerwinkle E. Defects in the LDL receptor gene affect Lp(a) lipoprotein levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci USA 1989; 86:4171-4174
28. White AL, Hixson JE, Rainwater DL, Lanford RE. Molecular basis for 'null' lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon. J Biol Chem 1994; 269:9060-9066
29. Brunner C, Lobentanz EM, Petho-Schramm A, Ernst A, Kang C, Dieplinger H, et al. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells. J Biol Chem 1996; 271:32403-32410.
30. Lobentanz EM, Krasznai K, Gruber A, Brunner C, Muller HJ, Sattler J et al. Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells. Biochemistry 1998; 37:5417-5425. Using HepG2 cells stably transfected with rec apo(a) the authors demonstrated by cell biology methods that apo(a) does not assemble with apo B-100 within these cells and confirm the inverse relation of kringle IV-2 repeat number with secretion efficiency of apo(a) in stably transfected apo(a) expressing cells
31. Wade DP, Clarke JG, Lindahl GE, Liu AC, Zysow BR, et al 5′ control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family Proc Natl Acad Sci USA 1993, 90:1369-1373.
32. Mancini FP, Mooser V, Guerra R, Hobbs HH Sequence microheterogeneity in apolipoprotein(a) gene repeats and the relationship to plasma Lp(a) levels Hum Mol Genet 1995; 4:1535-1542
33. Suzuki K, Kuriyama M, Saito T, Ichinose A. Plasma lipoprotein(a) levels and expression of the apolipoproiein(a) gene are dependent on the nucleotide polymorphisms in its 5′-flanking region. J Clin Invest 1997; 99:1361-1366. A careful molecular study demonstrating differences in promoter activities between 5′apo(a) haplotypes.
34. Prins J, Leus FR, Van der Hoek YY, Kastelein JJ, Bouma BN, Rijn HJ. The identification and significance of a Thr-> Pro polymorphism in kringle IV type 8 of apolipoprotein(a). Thromb Haemost 1997; 77:949-954. Identification of a polymorphism in K IV-8. The authors claim an effect of the polymorphism on functional properties (lysine binding)
35. 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 Mol Basis Dis 1994; 1227.41-45
36. Kraft HG, Haibach C, Lingenhel A, Brunner C, Trommsdorff M, et al. Sequence polymorphism in kringle IV 37 in linkage disequilibrium with the apolipoprotein(a) size polymorphism. Hum Genet 1995, 95:275-282.
37. 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; 2:361-366.
38. 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; 6:1099-1107 This article reports the amazing observation that linkage disequilibria exist at the apo(a) locus which extend over the kringle IV-2 VNTR.
39. Trommsdorff M, Köchl S, Lingenhel A, Kronenberg F, Delport R, Vermaak H et al. A pentanucleotide repeat polymorphism in the 5′ control region of the apohpoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians J Clin Invest 1995; 96:150-157.
40. Mooser V, Mancini FP, Bopp S, Schramm AP, Guerra R, Boerwinkle E, et al. Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma Hum Mol Genet 1995; 4:173-181.
41. Bopp S, Kochl S, Acquati F, Magnaghi P, Petho Schramm A, et al. Ten allelic apolipoprotein[a] 5′ flanking fragments exhibit comparable promoter activities in HepG2 cells J Lipid Res 1995; 36:1721-1728.
42. 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 1995, 15:58-64.
43. 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; 7:257-264. Extension of known in-vitro effect of the +93 C/T polymorphism in apo(a) to the in-vivo situation with important conceptual implications.
44. White AL, Guerra B, Lanford RE. Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum. J Biol Chem 1997; 272:5048-5055. In this study White and collegues further elucidate the mechanism(s) which relate kringle IV repeat number to Lp(a) concentrations.
45. Cox LA, Jett C, Hixson JE. Molecular basis of an apolipoprotein[a] null allele: a splice site mutation is associated with deletion of a single exon J Lipid Res 1998, 39:1319-1326 First molecular characterization of an apo(a) null allele. A splice site mutation in a baboon results in a truncated apo(a) not secreted from cells
46. Pesole G, Gerardi A, Di Jeso F, Saccone C The peculiar evolution of apolipoprotein(a) in human and rhesus macaque. Genetics 1994; 136:255-260.
47. Laplaud PM, Beaubatie L, Rall SC, Luc G, Saboureau M. Lipoprotein (a) is the major apoB-containing lipoprotein in the plasma of a hibernator, the hedgehog (Ennaceus europaeus) J Lipid Res 1988, 29:1157-1170.
48. Lawn RM, Boonmark NW, Schwartz K, Lindahl GE, Wade DP, Byrne CD, et al. The recurring evolution of lipoprotein(a). Insights from cloning of hedgehog apolipoprotein(a). J Biol Chem 1995; 270:24004-24009.
49. Lawn RM, Schwartz K, Patthy L. Convergent evolution of apolipoprotein(a) in primates and hedgehog. Proc Natl Acad Sci U S A 1997; 94:11992-11997. An in-depth analysis of the phylogenetic relation and evolutionary history of apo(a) genes. Together with a preceding paper describing the cloning of hedgehog apo(a) this is an important contribution to our understanding of protein evolution. The authors demonstrate that apo(a) genes have evolved twice independently at different times in phylogenetically distant species and amazingly both have been modelled to allow their products to interact specifically with apo B in LDL thereby forming the Lp(a) particle.
50. Tomlinson JE, McLean JW, Lawn RM. Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis J Biol Chem 1989; 264:5957-5965.
51. Chenivesse X, Huby T, Wickins J, Chapman J, Thillet J. Molecular cloning of the cDNA encoding the carboxy-terminal domain of chimpanzee apolipoprotein(a): an Asp57-> Asn mutation in kringle IV-10 is associated with poor fibrin binding Biochemistry 1998, 37:7213-7223 This paper describes the cDNA sequence of the kringle IV-3 to 10 and protease domains of chimpanzee and human gene and associates residue 57 in kringle IV-10 with fibrin binding.