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. 1996 Jul 15;98(2):372–377. doi: 10.1172/JCI118802

Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease.

X L Wang 1, S X Liu 1, R M McCredie 1, D E Wilcken 1
PMCID: PMC507440  PMID: 8755647

Abstract

Elevated HDL-cholesterol (C) and apo AI are associated with decreased coronary artery disease (CAD) risk. We determined distributions of two MspI polymorphisms of the apo AI gene, associated in other studies with increased HDL-C, among 644 patients aged < or = 65 years in relation to circulating lipids and CAD severity assessed angiographically. The rare allele distributions at both sites were in Hardy-Weinberg equilibrium in these patients but the base changes were not associated with HDL-C and apo AI levels. However, patients homozygous for the -75 bp substitution were more likely to have one or more significantly diseased vessels (> 50% luminal obstruction)(OR: 4.75, 95%CI: 1.10- 20.46) as also were patients with the rare +83 bp alleles (OR: 2.56, 95%CI: 1.13-5.81). While there was an additive effect of the two polymorphisms to have severe CAD (OR: 6.33, 95%CI: 1.33-30.02), the polymorphism at +83 bp remained significant in predicting CAD severity after adjusting for other variables in a logistic regression analysis (OR: 2.95, 95%CI: 1.26-6.90), which was also strongly associated with the positive family CAD history (P = 0.009). We conclude that patients with these base changes in this Australian coronary population do not have increased HDL-C and apo AI levels but do have more severe CAD.

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Selected References

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  1. Angotti E., Mele E., Costanzo F., Avvedimento E. V. A polymorphism (G-->A transition) in the -78 position of the apolipoprotein A-I promoter increases transcription efficiency. J Biol Chem. 1994 Jul 1;269(26):17371–17374. [PubMed] [Google Scholar]
  2. Assmann G., von Eckardstein A., Funke H. High density lipoproteins, reverse transport of cholesterol, and coronary artery disease. Insights from mutations. Circulation. 1993 Apr;87(4 Suppl):III28–III34. [PubMed] [Google Scholar]
  3. Asztalos B. F., Roheim P. S. Presence and formation of 'free apolipoprotein A-I-like' particles in human plasma. Arterioscler Thromb Vasc Biol. 1995 Sep;15(9):1419–1423. doi: 10.1161/01.atv.15.9.1419. [DOI] [PubMed] [Google Scholar]
  4. Badimon J. J., Fuster V., Badimon L. Role of high density lipoproteins in the regression of atherosclerosis. Circulation. 1992 Dec;86(6 Suppl):III86–III94. [PubMed] [Google Scholar]
  5. Barre D. E., Guerra R., Verstraete R., Wang Z., Grundy S. M., Cohen J. C. Genetic analysis of a polymorphism in the human apolipoprotein A-I gene promoter: effect on plasma HDL-cholesterol levels. J Lipid Res. 1994 Jul;35(7):1292–1296. [PubMed] [Google Scholar]
  6. Blangero J., Williams-Blangero S., Mahaney M. C. Multivariate genetic analysis of apo AI concentration and HDL subfractions: evidence for major locus pleiotropy. Genet Epidemiol. 1993;10(6):617–622. doi: 10.1002/gepi.1370100648. [DOI] [PubMed] [Google Scholar]
  7. Breslow J. L., Eisenberg S., Brinton E. A. Metabolic determinants of low HDL-C levels. Ann N Y Acad Sci. 1993 Mar 15;676:157–162. doi: 10.1111/j.1749-6632.1993.tb38731.x. [DOI] [PubMed] [Google Scholar]
  8. Falcone D., Andrews D. W. Both the 5' untranslated region and the sequences surrounding the start site contribute to efficient initiation of translation in vitro. Mol Cell Biol. 1991 May;11(5):2656–2664. doi: 10.1128/mcb.11.5.2656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Forte T. M., Goth-Goldstein R., Nordhausen R. W., McCall M. R. Apolipoprotein A-I-cell membrane interaction: extracellular assembly of heterogeneous nascent HDL particles. J Lipid Res. 1993 Feb;34(2):317–324. [PubMed] [Google Scholar]
  10. Forte T. M., McCall M. R. The role of apolipoprotein A-I-containing lipoproteins in atherosclerosis. Curr Opin Lipidol. 1994 Oct;5(5):354–364. doi: 10.1097/00041433-199410000-00007. [DOI] [PubMed] [Google Scholar]
  11. Lopez-Miranda J., Ordovas J. M., Espino A., Marin C., Salas J., Lopez-Segura F., Jimenez-Pereperez J., Perez-Jimenez F. Influence of mutation in human apolipoprotein A-1 gene promoter on plasma LDL cholesterol response to dietary fat. Lancet. 1994 May 21;343(8908):1246–1249. doi: 10.1016/s0140-6736(94)92149-0. [DOI] [PubMed] [Google Scholar]
  12. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pagani F., Giudici G. A., Baralle F. E., Vergani C. Association of a polymorphism in the Apo AI gene promoter with hyperalphalipoproteinemia. Eur J Epidemiol. 1992 May;8 (Suppl 1):54–58. doi: 10.1007/BF00145350. [DOI] [PubMed] [Google Scholar]
  14. Papazafiri P., Ogami K., Ramji D. P., Nicosia A., Monaci P., Cladaras C., Zannis V. I. Promoter elements and factors involved in hepatic transcription of the human ApoA-I gene positive and negative regulators bind to overlapping sites. J Biol Chem. 1991 Mar 25;266(9):5790–5797. [PubMed] [Google Scholar]
  15. Paul-Hayase H., Rosseneu M., Robinson D., Van Bervliet J. P., Deslypere J. P., Humphries S. E. Polymorphisms in the apolipoprotein (apo) AI-CIII-AIV gene cluster: detection of genetic variation determining plasma apo AI, apo CIII and apo AIV concentrations. Hum Genet. 1992 Feb;88(4):439–446. doi: 10.1007/BF00215679. [DOI] [PubMed] [Google Scholar]
  16. Shemer R., Walsh A., Eisenberg S., Breslow J. L., Razin A. Tissue-specific methylation patterns and expression of the human apolipoprotein AI gene. J Biol Chem. 1990 Jan 15;265(2):1010–1015. [PubMed] [Google Scholar]
  17. Sigurdsson G., Jr, Gudnason V., Sigurdsson G., Humphries S. E. Interaction between a polymorphism of the apo A-I promoter region and smoking determines plasma levels of HDL and apo A-I. Arterioscler Thromb. 1992 Sep;12(9):1017–1022. doi: 10.1161/01.atv.12.9.1017. [DOI] [PubMed] [Google Scholar]
  18. Smith J. D., Brinton E. A., Breslow J. L. Polymorphism in the human apolipoprotein A-I gene promoter region. Association of the minor allele with decreased production rate in vivo and promoter activity in vitro. J Clin Invest. 1992 Jun;89(6):1796–1800. doi: 10.1172/JCI115783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sonenberg N. mRNA translation: influence of the 5' and 3' untranslated regions. Curr Opin Genet Dev. 1994 Apr;4(2):310–315. doi: 10.1016/s0959-437x(05)80059-0. [DOI] [PubMed] [Google Scholar]
  20. Stampfer M. J., Sacks F. M., Salvini S., Willett W. C., Hennekens C. H. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991 Aug 8;325(6):373–381. doi: 10.1056/NEJM199108083250601. [DOI] [PubMed] [Google Scholar]
  21. Steinmetz J., Boerwinkle E., Gueguen R., Visvikis S., Henny J., Siest G. Multivariate genetic analysis of high density lipoprotein particles. Atherosclerosis. 1992 Feb;92(2-3):219–227. doi: 10.1016/0021-9150(92)90281-k. [DOI] [PubMed] [Google Scholar]
  22. Talmud P. J., Ye S., Humphries S. E. Polymorphism in the promoter region of the apolipoprotein AI gene associated with differences in apolipoprotein AI levels: the European Atherosclerosis Research Study. Genet Epidemiol. 1994;11(3):265–280. doi: 10.1002/gepi.1370110305. [DOI] [PubMed] [Google Scholar]
  23. Tribble D. L., Krauss R. M. HDL and coronary artery disease. Adv Intern Med. 1993;38:1–29. [PubMed] [Google Scholar]
  24. Tuteja R., Tuteja N., Melo C., Casari G., Baralle F. E. Transcription efficiency of human apolipoprotein A-I promoter varies with naturally occurring A to G transition. FEBS Lett. 1992 Jun 8;304(1):98–101. doi: 10.1016/0014-5793(92)80597-a. [DOI] [PubMed] [Google Scholar]
  25. Wang X. L., Badenhop R., Humphrey K. E., Wilcken D. E. C to T and/or G to A transitions are responsible for loss of a MspI restriction site at the 5'-end of the human apolipoprotein AI gene. Hum Genet. 1995 Apr;95(4):473–474. doi: 10.1007/BF00208984. [DOI] [PubMed] [Google Scholar]
  26. Wang X. L., Badenhop R., Humphrey K. E., Wilcken D. E. New MspI polymorphism at +83 bp of the human apolipoprotein AI gene: association with increased circulating high density lipoprotein cholesterol levels. Genet Epidemiol. 1996;13(1):1–10. doi: 10.1002/(SICI)1098-2272(1996)13:1<1::AID-GEPI1>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  27. Wang X. L., Dudman N. P., Blades B. L., Wilcken D. E. Changes in the immunoreactivity of Apo A-I during storage. Clin Chim Acta. 1989 Feb 22;179(3):285–293. doi: 10.1016/0009-8981(89)90091-0. [DOI] [PubMed] [Google Scholar]
  28. Wang X. L., Dudman N. P., Wilcken D. E. Enzyme-linked immunosorbent assay of apolipoprotein B in blood spotted onto filter paper, suitable for neonatal screening. Clin Chem. 1989 Jun;35(6):1000–1004. [PubMed] [Google Scholar]
  29. Wang X. L., Tam C., McCredie R. M., Wilcken D. E. Determinants of severity of coronary artery disease in Australian men and women. Circulation. 1994 May;89(5):1974–1981. doi: 10.1161/01.cir.89.5.1974. [DOI] [PubMed] [Google Scholar]
  30. Wang X. L., Wilcken D. E., Dudman N. P. An indirect sandwich ELISA for LP(a) in serum and dried blood spots. Clin Chim Acta. 1992 Apr 30;207(1-2):73–86. doi: 10.1016/0009-8981(92)90151-f. [DOI] [PubMed] [Google Scholar]
  31. Wilson P. W., Anderson K. M., Harris T., Kannel W. B., Castelli W. P. Determinants of change in total cholesterol and HDL-C with age: the Framingham Study. J Gerontol. 1994 Nov;49(6):M252–M257. doi: 10.1093/geronj/49.6.m252. [DOI] [PubMed] [Google Scholar]
  32. Xu C. F., Nanjee M. N., Savill J., Talmud P. J., Angelico F., Del Ben M., Antonini R., Mazzarella B., Miller N., Humphries S. E. Variation at the apolipoprotein (apo) AI-CIII-AIV gene cluster and apo B gene loci is associated with lipoprotein and apolipoprotein levels in Italian children. Am J Hum Genet. 1990 Sep;47(3):429–439. [PMC free article] [PubMed] [Google Scholar]

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