Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 May;50(5):1115–1128.

Nonsynonymous polymorphic sites in the apolipoprotein (apo) A-IV gene are associated with changes in the concentration of apo B- and apo A-I-containing lipoproteins in a normal population.

A von Eckardstein 1, H Funke 1, M Schulte 1, M Erren 1, H Schulte 1, G Assmann 1
PMCID: PMC1682587  PMID: 1349197

Abstract

The aims of this study were to detect polymorphic sites in the apolipoprotein (apo) A-IV gene, to establish their frequencies, to determine potential haplotypes, and to investigate the role of these polymorphisms in lipid metabolism. A sequencing study of four individuals led to the identification of two synonymous mutations (codons 9 and 54) and three nonsynonymous mutations (Val-8----Met, Gln360----His, and Thr347----Ser) and of a VNTR polymorphism within a series of three or four CTGT repeats in the noncoding region of exon 3. Frequencies of these polymorphisms were determined in 291 students by using naturally occurring (BstEII for the synonymous mutation in codon 54, HinfI for Thr347----Ser, and Fnu4HI for Gln360----His) or artificially introduced restriction-enzyme cutting sites (BstEII for the synonymous mutation in codon 9 and MamI for Val-8----Met), subsequent to PCR amplification. The four-base deletion/insertion polymorphism and its localization cis or trans to the mutations in codons 347 and 360 were studied by direct sequencing of PCR-amplified DNA from 87 students. Frequencies of the rarer alleles were .007 for apo A-IV-8:Met, .04 for the synonymous mutation in codon 9, .14 for the synonymous mutation in codon 54, .16 for apo A-IV347:Ser, .07 for apo A-IV360:His, and .39 for the four-base of insertion. Apo A-IV360:His in all cases was cis-localized to the (CTGT)3 repeat and apo A-IV347:Thr; and apo A-IV347:Ser was cis-localized to the (CTGT)4 repeat and apo A-IV360:Gln. Four haplotypes formed from these three polymorphic sites were thus found. The apo A-IV347:Ser allele was associated both with significantly lower plasma apo B concentrations in both sexes and with significantly lower LDL-cholesterol concentrations in men. Heterozygous carriers of apo A-IV360:His exhibited significantly higher concentrations of LDL-cholesterol and lower Lp(a) concentrations, compared with apo A-IV360:Gln homozygotes. We could not confirm the previously reported association of apo A-IV360:His with elevated HDL-cholesterol concentrations. In the population, the Val-8----Met polymorphism was not associated with significantly different lipid concentrations, but in a family study the Met-8 allele was associated with lower HDL-cholesterol and higher LDL-cholesterol concentrations. In conclusion, our results indicate an important role of the apo A-IV gene locus in the metabolism of apo B and, to a lesser extent, apo A-I containing lipoproteins.

Full text

PDF
1119

Images in this article

1117Figure 1
on p.1117
1118Figure 3
on p.1118
1118Figure 4
on p.1118
1119Figure 5
on p.1119
1120Figure 6
on p.1120
1121Figure 7
on p.1121

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anantharamaiah G. M., Venkatachalapathi Y. V., Brouillette C. G., Segrest J. P. Use of synthetic peptide analogues to localize lecithin:cholesterol acyltransferase activating domain in apolipoprotein A-I. Arteriosclerosis. 1990 Jan-Feb;10(1):95–105. doi: 10.1161/01.atv.10.1.95. [DOI] [PubMed] [Google Scholar]
  2. Beisiegel U., Utermann G. An apolipoprotein homolog of rat apolipoprotein A-IV in human plasma. Isolation and partial characterisation. Eur J Biochem. 1979 Feb 1;93(3):601–608. doi: 10.1111/j.1432-1033.1979.tb12860.x. [DOI] [PubMed] [Google Scholar]
  3. Bisgaier C. L., Sachdev O. P., Megna L., Glickman R. M. Distribution of apolipoprotein A-IV in human plasma. J Lipid Res. 1985 Jan;26(1):11–25. [PubMed] [Google Scholar]
  4. Boerwinkle E., Visvikis S., Chan L. Two polymorphisms for amino acid substitutions in the APOA4 gene. Nucleic Acids Res. 1990 Aug 25;18(16):4966–4966. doi: 10.1093/nar/18.16.4966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen C. H., Albers J. J. Activation of lecithin: cholesterol acyltransferase by apolipoproteins E-2, E-3, and A-IV isolated from human plasma. Biochim Biophys Acta. 1985 Oct 2;836(3):279–285. doi: 10.1016/0005-2760(85)90131-6. [DOI] [PubMed] [Google Scholar]
  6. Coleman R. T., Gonzalez P. A., Funke H., Assmann G., Levy-Wilson B., Frossard P. M. Polymorphisms in the apolipoprotein AI-CIII gene complex. Mol Biol Med. 1986 Jun;3(3):213–228. [PubMed] [Google Scholar]
  7. Dvorin E., Gorder N. L., Benson D. M., Gotto A. M., Jr Apolipoprotein A-IV. A determinant for binding and uptake of high density lipoproteins by rat hepatocytes. J Biol Chem. 1986 Nov 25;261(33):15714–15718. [PubMed] [Google Scholar]
  8. Eichner J. E., Kuller L. H., Ferrell R. E., Kamboh M. I. Phenotypic effects of apolipoprotein structural variation on lipid profiles: II. Apolipoprotein A-IV and quantitative lipid measures in the healthy women study. Genet Epidemiol. 1989;6(4):493–499. doi: 10.1002/gepi.1370060404. [DOI] [PubMed] [Google Scholar]
  9. Elshourbagy N. A., Walker D. W., Paik Y. K., Boguski M. S., Freeman M., Gordon J. I., Taylor J. M. Structure and expression of the human apolipoprotein A-IV gene. J Biol Chem. 1987 Jun 15;262(17):7973–7981. [PubMed] [Google Scholar]
  10. Ferrell R. E., Sepehrnia B., Kamboh M. I., VandeBerg J. L. Highly polymorphic apolipoprotein A-IV locus in the baboon. J Lipid Res. 1990 Jan;31(1):131–135. [PubMed] [Google Scholar]
  11. Francone O. L., Gurakar A., Fielding C. Distribution and functions of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in plasma lipoproteins. Evidence for a functional unit containing these activities together with apolipoproteins A-I and D that catalyzes the esterification and transfer of cell-derived cholesterol. J Biol Chem. 1989 Apr 25;264(12):7066–7072. [PubMed] [Google Scholar]
  12. Friedewald W. T., Levy R. I., Fredrickson D. S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972 Jun;18(6):499–502. [PubMed] [Google Scholar]
  13. Funke H., von Eckardstein A., Pritchard P. H., Albers J. J., Kastelein J. J., Droste C., Assmann G. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4855–4859. doi: 10.1073/pnas.88.11.4855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ghiselli G., Crump W. L., 3rd, Gotto A. M., Jr Binding of apoA-IV-phospholipid complexes to plasma membranes of rat liver. Biochem Biophys Res Commun. 1986 Aug 29;139(1):122–128. doi: 10.1016/s0006-291x(86)80088-2. [DOI] [PubMed] [Google Scholar]
  15. Goldberg I. J., Scheraldi C. A., Yacoub L. K., Saxena U., Bisgaier C. L. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. J Biol Chem. 1990 Mar 15;265(8):4266–4272. [PubMed] [Google Scholar]
  16. Green P. H., Glickman R. M., Riley J. W., Quinet E. Human apolipoprotein A-IV. Intestinal origin and distribution in plasma. J Clin Invest. 1980 Apr;65(4):911–919. doi: 10.1172/JCI109745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hanis C. L., Douglas T. C., Hewett-Emmett D. Apolipoprotein A-IV protein polymorphism: frequency and effects on lipids, lipoproteins, and apolipoproteins among Mexican-Americans in Starr County, Texas. Hum Genet. 1991 Jan;86(3):323–325. doi: 10.1007/BF00202422. [DOI] [PubMed] [Google Scholar]
  19. Hayden M. R., Kirk H., Clark C., Frohlich J., Rabkin S., McLeod R., Hewitt J. DNA polymorphisms in and around the Apo-A1-CIII genes and genetic hyperlipidemias. Am J Hum Genet. 1987 May;40(5):421–430. [PMC free article] [PubMed] [Google Scholar]
  20. Juneja R. K., Gahne B., Lukka M., Ehnholm C. A previously reported polymorphic plasma protein of dogs and horses, identified as apolipoprotein A-IV. Anim Genet. 1989;20(1):59–63. doi: 10.1111/j.1365-2052.1989.tb00842.x. [DOI] [PubMed] [Google Scholar]
  21. Karathanasis S. K. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6374–6378. doi: 10.1073/pnas.82.19.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kumar R., Barbacid M. Oncogene detection at the single cell level. Oncogene. 1988 Dec;3(6):647–651. [PubMed] [Google Scholar]
  23. Kumar R., Dunn L. L. Designed diagnostic restriction fragment length polymorphisms for the detection of point mutations in ras oncogenes. Oncogene Res. 1989;4(3):235–241. [PubMed] [Google Scholar]
  24. Lefevre M., Goudey-Lefevre J. C., Roheim P. S. Preferential redistribution of lipoprotein-unassociated apoA-IV to an HDL subpopulation with a high degree of LCAT modification. Lipids. 1989 Dec;24(12):1035–1038. doi: 10.1007/BF02544075. [DOI] [PubMed] [Google Scholar]
  25. Lohse P., Kindt M. R., Rader D. J., Brewer H. B., Jr Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene. J Biol Chem. 1990 Jun 15;265(17):10061–10064. [PubMed] [Google Scholar]
  26. Menzel H. J., Boerwinkle E., Schrangl-Will S., Utermann G. Human apolipoprotein A-IV polymorphism: frequency and effect on lipid and lipoprotein levels. Hum Genet. 1988 Aug;79(4):368–372. doi: 10.1007/BF00282179. [DOI] [PubMed] [Google Scholar]
  27. Menzel H. J., Kladetzky R. G., Assmann G. One-step screening method for the polymorphism of apolipoproteins A-I, A-II, and A-IV. J Lipid Res. 1982 Aug;23(6):915–922. [PubMed] [Google Scholar]
  28. Menzel H. J., Sigurdsson G., Boerwinkle E., Schrangl-Will S., Dieplinger H., Utermann G. Frequency and effect of human apolipoprotein A-IV polymorphism on lipid and lipoprotein levels in an Icelandic population. Hum Genet. 1990 Mar;84(4):344–346. doi: 10.1007/BF00196231. [DOI] [PubMed] [Google Scholar]
  29. Nowicka G., Brüning T., Böttcher A., Kahl G., Schmitz G. Macrophage interaction of HDL subclasses separated by free flow isotachophoresis. J Lipid Res. 1990 Nov;31(11):1947–1963. [PubMed] [Google Scholar]
  30. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  31. Sandkamp M., Funke H., Schulte H., Köhler E., Assmann G. Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age. Clin Chem. 1990 Jan;36(1):20–23. [PubMed] [Google Scholar]
  32. Sandkamp M., Tambyrajah B., Schriewer H., Assmann G. Simplified turbidimetric determination of apolipoproteins A-I, A-II and B using a microtitre method. J Clin Chem Clin Biochem. 1988 Nov;26(11):685–688. doi: 10.1515/cclm.1988.26.11.685. [DOI] [PubMed] [Google Scholar]
  33. Savion N., Gamliel A. Binding of apolipoprotein A-I and apolipoprotein A-IV to cultured bovine aortic endothelial cells. Arteriosclerosis. 1988 Mar-Apr;8(2):178–186. doi: 10.1161/01.atv.8.2.178. [DOI] [PubMed] [Google Scholar]
  34. Stein O., Stein Y., Lefevre M., Roheim P. S. The role of apolipoprotein A-IV in reverse cholesterol transport studied with cultured cells and liposomes derived from an ether analog of phosphatidylcholine. Biochim Biophys Acta. 1986 Aug 14;878(1):7–13. doi: 10.1016/0005-2760(86)90337-1. [DOI] [PubMed] [Google Scholar]
  35. Steinmetz A., Barbaras R., Ghalim N., Clavey V., Fruchart J. C., Ailhaud G. Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells. J Biol Chem. 1990 May 15;265(14):7859–7863. [PubMed] [Google Scholar]
  36. Steinmetz A., Utermann G. Activation of lecithin: cholesterol acyltransferase by human apolipoprotein A-IV. J Biol Chem. 1985 Feb 25;260(4):2258–2264. [PubMed] [Google Scholar]
  37. Tenkanen H., Lukka M., Jauhiainen M., Metso J., Baumann M., Peltonen L., Ehnholm C. The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360. Arterioscler Thromb. 1991 Jul-Aug;11(4):851–856. doi: 10.1161/01.atv.11.4.851. [DOI] [PubMed] [Google Scholar]
  38. Utermann G., Beisiegel U. Apolipoprotein A-IV: a protein occurring in human mesenteric lymph chylomicrons and free in plasma. Isolation and quantification. Eur J Biochem. 1979 Sep;99(2):333–343. doi: 10.1111/j.1432-1033.1979.tb13261.x. [DOI] [PubMed] [Google Scholar]
  39. Weinberg R. B., Jordan M. K. Effects of phospholipid on the structure of human apolipoprotein A-IV. J Biol Chem. 1990 May 15;265(14):8081–8086. [PubMed] [Google Scholar]
  40. Weinberg R. B., Jordan M. K., Steinmetz A. Distinctive structure and function of human apolipoprotein variant ApoA-IV-2. J Biol Chem. 1990 Oct 25;265(30):18372–18378. [PubMed] [Google Scholar]
  41. Weinberg R. B., Patton C. S. Binding of human apolipoprotein A-IV to human hepatocellular plasma membranes. Biochim Biophys Acta. 1990 May 22;1044(2):255–261. doi: 10.1016/0005-2760(90)90311-k. [DOI] [PubMed] [Google Scholar]
  42. Weinberg R. B., Scanu A. M. Isolation and characterization of human apolipoprotein A-IV from lipoprotein-depleted serum. J Lipid Res. 1983 Jan;24(1):52–59. [PubMed] [Google Scholar]
  43. Weisgraber K. H., Bersot T. P., Mahley R. W. Isolation and characterization of an apoprotein from the d less than 1.006 lipoproteins of human and canine lymph homologous with the rat A-IV apoprotein. Biochem Biophys Res Commun. 1978 Nov 14;85(1):287–292. doi: 10.1016/s0006-291x(78)80041-2. [DOI] [PubMed] [Google Scholar]
  44. Wojciechowski A. P., Farrall M., Cullen P., Wilson T. M., Bayliss J. D., Farren B., Griffin B. A., Caslake M. J., Packard C. J., Shepherd J. Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24. Nature. 1991 Jan 10;349(6305):161–164. doi: 10.1038/349161a0. [DOI] [PubMed] [Google Scholar]
  45. de Knijff P., Rosseneu M., Beisiegel U., de Keersgieter W., Frants R. R., Havekes L. M. Apolipoprotein A-IV polymorphism and its effect on plasma lipid and apolipoprotein concentrations. J Lipid Res. 1988 Dec;29(12):1621–1627. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES