Human Genetics

, Volume 86, Issue 6, pp 607–614

Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups

  • C. Sandholzer
  • D. M. Hallman
  • N. Saha
  • G. Sigurdsson
  • C. Lackner
  • A. Császár
  • E. Boerwinkle
  • G. Utermann
Original Investigations

Summary

Apolipoprotein(a) [apo(a)] exhibits a genetic size polymorphism explaining about 40% of the variability in lipoprotein(a) [Lp(a)] concentration in Tyroleans. Lp(a) concentrations and apo(a) phenotypes were determined in 7 ethnic groups (Tyrolean, Icelandic, Hungarian, Malay, Chinese, Indian, Black Sudanese) and the effects of the apo(a) size polymorphism on Lp(a) levels were estimated in each group. Average Lp(a) concentrations were highly significantly different among these populations, with the Chinese (7.0mg/dl) having the lowest and the Sudanese (46mg/dl) the highest levels. Apo(a) phenotype and derived apo(a) allele frequencies were also significantly different among the populations. Apo(a) isoform effects on Lp(a) levels were not significantly different among populations. Lp(a) levels were however roughly twice as high in the same phenotypes in the Indians, and several times as high in the Sudanese, compared with Caucasians. The size variation of apo(a) explains from 0.77 (Malays) to only 0.19 (Sudanese) of the total variability in Lp(a) levels. Together these data show (I) that there is considerable heterogeneity of the Lp(a) polymorphism among populations, (II) that differences in apo(a) allele frequencies alone do not explain the differences in Lp(a) levels among populations and (III) that in some populations, e.g. Sudanese Blacks, Lp(a) levels are mainly determined by factors that are different from the apo(a) size polymorphism.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Berg K (1963) A new serum type system in man — the Lp-system. Acta Pathol Microbiol Immunol Scand 59:369–382Google Scholar
  2. Boerwinkle E, Menzel HJ, Kraft HG, Utermann G (1989) Genetics of the quantitative Lp(a) lipoprotein trait. III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation. Hum Genet 82:73–78Google Scholar
  3. Conover WJ (1980) Practical nonparametric statistics. Wiley, New YorkGoogle Scholar
  4. Dixon WJ (ed) (1988) BMDP statistical software. Manual (vols 1 and 2). University of California Press, BerkleyGoogle Scholar
  5. Drayna DT, Hegele RA, Hass PE, Wu LL, Emi M, Eaton DL, Lawn RM, Williams RR, White RL, Lalouel JM (1988) Genetic linkage between lipoprotein (a) phenotype and a DNA polymorphism in the plasminogen gene. Genomics 3:230:236Google Scholar
  6. Frank SL, Klisak I, Sparkes RS, Mohandas T, Tomlinson JE, Mc-Lean JW, Lawn RM, Lusis AJ (1988) The apolipoprotein(a) gene resides on human chromosome 6q26–27 in close proximity to the homologous gene for plasminogen. Hum Genet 79:352–356Google Scholar
  7. Gaubatz JW, Ghanem KI, Guevara J Jr, Nava ML, Patsch W, Morrisett JD (1990) Polymorphic forms of human apolipoprotein(a): inheritance and relationship of their molecular weights to plasma levels of lipoprotein (a). J Lipid Res 31:603–613Google Scholar
  8. Gavish D, Azrolan N, Breslow JL (1989) Plasma Lp(a) concentration is inversely correlated with the ratio of kringle IV/kringle V encoding domains in the apo(a) gene. J Clin Invest 84:2021–2027Google Scholar
  9. Guyton JR, Dahlen GH, Patsch W, Kautz JA, Gotto AM Jr (1985) Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B. Arteriosclerosis 5:265–272Google Scholar
  10. Hasstedt SJ, Williams RR (1986) Three alleles for the quantitative Lp(a) Genet Epidemiol 3:53–55Google Scholar
  11. Hasstedt SJ, Wilson DE, Edwards CQ, Cannon WN, Carmelli D, Williams RR (1983) The genetics of quantitative plasma Lp(a): analysis of a large pedigree. Am J Med Genet 16:179–188Google Scholar
  12. Iselius L, Dahlen GH, Faire U de, Lindman T (1981) Complex segregation analysis of the Lp(a) (pre-β)-lipoprotein trait. Clin Genet 20:147–151Google Scholar
  13. Kraft HG, Dieplinger H, Hoye E, Utermann G (1988) Lp(a) phenotyping by immunoblotting with polyclonal and monoclonal antibodies. Arteriosclerosis 8:212–216Google Scholar
  14. Kratzin H, Armstrong VW, Niehaus M, Hilschman N, Seidel D (1987) Structural relationship of an apolipoprotein(a) phenotype (570kDa) to plasminogen: homologous kringle domains are linked by carbohydrate-rich regions. Biol Chem Hoppe-Seyler 368:1533–1544Google Scholar
  15. Krempler F, Kostner GM, Bolzano K, Sandhofer F (1980) Turnover of lipoprotein (a) in man. J Clin Invest 65:1483–1490Google Scholar
  16. Lindahl G, Gersdorf E, Menzel HJ, Duba C, Cleve H, Humphries S, Utermann G (1989) The gene for the Lp(a) specific glycoprotein is closely linked to the gene for plasminogen on chromosome 6. Hum Genet 81:149–152Google Scholar
  17. Lindahl G, Gersdorf E, Menzel HJ, Seed M, Humphries S, Utermann G (1990) Variation in the size of human apolipoprotein (a) is due to hypervariable region in the gene. Hum Genet 84:563–567Google Scholar
  18. McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM (1987) cDNA sequence of human apolipoprotein (a) is homologous to plasminogen. Nature 300:132–137Google Scholar
  19. Menzel HJ, Dieplinger H, Lackner C, Hoppichler F, Lloyd JK, Muller DR, Labeur C, Talmud PJ, Utermann G (1990) Abetalipoproteinemia with an Apo B-100 lipoprotein (a) glycoprotein complex in plasma — indication for an assembly defect. J Biol Chem 265:981–986Google Scholar
  20. Morton NE, Berg K, Dahlen G, Ferrel RE, Rhoads GG (1985) Genetics of the Lp-lipoprotein in Japanese-Americans. Genet Epidemiol 2:113–121Google Scholar
  21. Neter J, Wasserman W (1974) Applied linear statistical model. Irwin, Homewood, 111Google Scholar
  22. Parra H-J, Luyeye I, Bouramoue C, Demarquilly C, Fruchart J-C (1987) Black-white differences in serum Lp(a) lipoprotein levels. Clin Chim Acta 167:27–31Google Scholar
  23. Patthy L (1985) Evolution of the proteases of the blood coagulation and fibrinolysis by assembly from modules. Cell 41:657–663Google Scholar
  24. Scanu AM, Fless GM (1990) Lipoprotein(a). Heterogeneity and biological relevance. J Clin Invest 85:1709–1715Google Scholar
  25. Sing CF, Schultz JS, Shreffler DC (1974) Genetics of the Lp(a) antigen. II. A family study and proposed models of genetic control. Am J Hum Genet 38:47–56Google Scholar
  26. Sigurdsson G (1987) Lipids and diet in relation to cardiovascular disease in Iceland. Br J Clin Pract 41 [Suppl 54]:54Google Scholar
  27. Snedecor GW, Cochran WG (1980) Statistical methods, 7th edn. Iowa State University Press, Ames, IowaGoogle Scholar
  28. Utermann G (1987) Apolipoproteins, quantitative lipoprotein traits and multifactorial hyperlipidaemia. In: Bock G, Collins GM (eds) Molecular approaches to human polygenic disease. (Ciba Foundation Symposium 130) Wiley, Chichester, pp 52–69Google Scholar
  29. Utermann G (1989) The mysteries of lipoprotein (a). Science246:904–910Google Scholar
  30. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C (1987) Lp(a) glycoprotein phenotype. Inheritance and relation to Lp(a)-lipoprotein concentration in plasma. J Clin Invest 80:458–465Google Scholar
  31. Utermann G, Kraft HG, Menzel HJ, Hopferwieser T, Seitz C (1988a) Genetics of the quantitative Lp(a) lipoprotein trait. I. Relation of Lp(a) glycoprotein phenotypes to Lp (a) lipoproein concentration in plasma. Hum Genet 78:41–46Google Scholar
  32. Utermann G, Duba C, Menzel HJ (1988b) Genetics of the quantitative Lp(a) lipoprotein trait. II. Inheritance of Lp(a) glycoprotein phenotypes. Hum Genet 78:47–50Google Scholar
  33. Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boerwinkle E (1989) Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci USA 86:4171–4174Google Scholar
  34. Vogel F, Motulsky AG (1986) Human genetics — problems and approaches, 2nd edn. Springer, Berlin Heidelberg New YorkGoogle Scholar
  35. Weitkamp LR, Guttormsen SA, Schultz JS (1988) Linkage between the loci for the Lp(a) lipoprotein (LP) and plasminogen (PLG) Hum Genet 79:80–82Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • C. Sandholzer
    • 1
  • D. M. Hallman
    • 2
  • N. Saha
    • 3
  • G. Sigurdsson
    • 4
  • C. Lackner
    • 1
  • A. Császár
    • 1
  • E. Boerwinkle
    • 2
  • G. Utermann
    • 1
  1. 1.Institut für Medizinische Biologie und Humangenetik der UniversitätInnsbruckAustria
  2. 2.Center for Demographic and Population GeneticsUniversity of Texas, Health Science CenterHoustonUSA
  3. 3.Division of GeneticsNational University HospitalSingaporeSingapore
  4. 4.Reykjavik City HospitalReykjavikIceland

Personalised recommendations