Skip to main content

Advertisement

SpringerLink
Log in

ApoE ε2/ε3/ε4 polymorphism, ApoC-III/ApoE ratio and metabolic syndrome

  • Original
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Triglyceride-rich lipoproteins contain both apolipoproteins E (ApoE) and C-III (ApoC-III), which show opposite functional properties. The relationships between the ApoE (ε2/ε3/ε4) gene polymorphism and ApoC-III/ApoE ratio has never been investigated. A large population (n=552) of cardiovascular patients, without diabetes and/or lipid-lowering therapy, with or without metabolic syndrome (MetSyn), was genotyped for ε2/ε3/ε4 polymorphism and their ApoCIII/ApoE ratio was evaluated. A second group of patients (n=76) with peripheral artery disease was also genotyped and their ApoC-III/ApoE ratios were measured in HDL and non-HDL fractions. Subjects with E2 had higher and E4 carriers lower TG,ApoE and ApoC-III levels, respectively. The ApoCIII/ ApoE ratio showed an opposite trend, gradually increasing from E2/E2 to E4/E4 subjects. MetSyn patients also had an elevated ApoC-III/ApoE ratio and E4 carriers were more frequent in MetSyn patients (OR 2.08 with a 95%CI 1.22–3.5). The distribution of ApoC-III/ApoE ratio was confirmed also in the second group, with lower values in E2/E3 and higher in E3/E4 subjects. Similar results were obtained for the concentrations measured in non-HDL fractions, but not in the HDL fractions. ApoE ε2/ε/ε4 gene polymorphism is a determinant of the relative proportion of apolipoprotein C-III to E. Carriers of the unfavourable E4 allele present the highest ApoCIII/ApoE ratio and are twofold more frequent among individuals affected by MetSyn.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Song Y, Stampfer MJ, Liu S (2004) Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med 141:137–147

    PubMed  Google Scholar 

  2. Paik YK, Chang DJ, Reardon CA et al (1985) Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci U S A 82:3445–3449

    Article  PubMed  CAS  Google Scholar 

  3. Greenow K, Pearce NJ, Ramji DP (2005) The key role of apolipoprotein E in atherosclerosis. J Mol Med 83:329–342

    Article  PubMed  CAS  Google Scholar 

  4. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537

    Article  PubMed  CAS  Google Scholar 

  5. Dallongeville J, Lussier-Cacan S, Davignon J (1992) Modulation of plasma triglyceride levels by ApoE phenotype: a meta-analysis. J Lipid Res 33:447–454

    PubMed  CAS  Google Scholar 

  6. Ordovas JM, Schaefer EJ (2000) Genetic determinants of plasma lipid response to dietary intervention: the role of the APOA1/C3/A4 gene cluster and the ApoE gene. Br J Nutr 83[Suppl 1]:S127–136

    PubMed  CAS  Google Scholar 

  7. Mahley RW, Ji ZS (1999) Remnant lipoprotein metabolism: key pathways involving cell-surface heparin sulfate proteoglycans and apolipoprotein E. J Lipid Res 40:1–16

    PubMed  CAS  Google Scholar 

  8. van den Elzen P, Garg S, Leon L et al (2005) Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437:906–910

    Article  PubMed  CAS  Google Scholar 

  9. Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468–471

    Article  PubMed  CAS  Google Scholar 

  10. Zhang SH, Reddick RL, Burkey B, Maeda N (1994) Dietinduced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption. J Clin Invest 94:937–945

    Article  PubMed  CAS  Google Scholar 

  11. Meir KS, Leitersdorf E (2004) Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress. Arterioscler Thromb Vasc Biol 24:1006–1014

    Article  PubMed  CAS  Google Scholar 

  12. Morrow JA, Segall ML, Lund-Katz S et al (2000) Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 39:11657–11666

    Article  PubMed  CAS  Google Scholar 

  13. Cohn JS, Marcoux C, Davignon J (1999) Detection, quantification, and characterization of potentially atherogenic triglyceride-rich remnant lipoproteins. Arterioscler Thromb Vasc Biol 19:2474–2486

    PubMed  CAS  Google Scholar 

  14. Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37:268–285

    PubMed  CAS  Google Scholar 

  15. Jong MC, Hofker MH, Havekes LM (1999) Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 19:472–484

    PubMed  CAS  Google Scholar 

  16. McConathy WJ, Gesquiere JC, Bass H et al (1992) Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J Lipid Res 33:995–1003

    PubMed  CAS  Google Scholar 

  17. Ginsberg HN, Le NA, Goldberg IJ et al (1986) Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 78:1287–1295

    Article  PubMed  CAS  Google Scholar 

  18. Kawakami A, Aikawa M, Alcaide P et al (2006) Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation 114:681–687

    Article  PubMed  CAS  Google Scholar 

  19. Hodis HN, Mack WJ (1998) Triglyceride-rich lipoproteins and progression of atherosclerosis. Eur Heart J 19[Suppl A]:A40–44

    PubMed  CAS  Google Scholar 

  20. Sacks FM, Alaupovic P, Moye LA et al (2000) VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 102:1886–1892

    PubMed  CAS  Google Scholar 

  21. Cohn JS, Patterson BW, Uffelman KD et al (2004) Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab 89:3949–3955

    Article  PubMed  CAS  Google Scholar 

  22. Olivieri O, Stranieri C, Bassi A et al (2002) ApoC-III gene polymorphisms and risk of coronary artery disease. J Lipid Res 43:1450–1457

    Article  PubMed  CAS  Google Scholar 

  23. Olivieri O, Bassi A, Stranieri C et al (2003) Apolipoprotein CIII, metabolic syndrome, and risk of coronary artery disease. J Lipid Res 44:2374–2381

    Article  PubMed  CAS  Google Scholar 

  24. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497

    Article  Google Scholar 

  25. Zee RY, Cook NR, Cheng S et al (2004) Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. Hum Mol Genet 13:389–396

    Article  PubMed  CAS  Google Scholar 

  26. Eichner JE, Dunn ST, Perveen G et al (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495

    Article  PubMed  Google Scholar 

  27. Scuteri A, Najjar SS, Muller D et al (2005) ApoE4 allele and the natural history of cardiovascular risk factors. Am J Physiol Endocrinol Metab 289:E322–327

    Article  PubMed  CAS  Google Scholar 

  28. Hallman DM, Boerwinkle E, Saha N et al (1991) The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 49:338–349

    PubMed  CAS  Google Scholar 

  29. Hiukka A, Fruchart-Najib J, Leinonen E et al (2005) Alterations of lipids and apolipoprotein CIII in very low density lipoprotein subspecies in type 2 diabetes. Diabetologia 48:1207–1215

    Article  PubMed  CAS  Google Scholar 

  30. Tian Y, Long SY, Xu YH et al (2005) Study on ApoE gene polymorphism and subclasses of serum high density lipoprotein in type IV hyperlipidemia [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22:96–98

    PubMed  CAS  Google Scholar 

  31. Tilly P, Sass C, Vincent-Viry M et al (2003) Biological and genetic determinants of serum apolipoprotein CIII concentration. Reference limits from the Stanislas Cohort. J Lipid Res 44:430–436

    Article  PubMed  CAS  Google Scholar 

  32. Stephan ZF, Gibson JC, Hayes KC (1986) The apo E/apo CIII molar ratio affects removal of cholesterol ester from modified human lipoproteins injected into cebus monkeys. Life Sci 38:1383–1392

    Article  PubMed  CAS  Google Scholar 

  33. Gregg RE, Zech LA, Schaefer EJ et al (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest 78:815–821

    Article  PubMed  CAS  Google Scholar 

  34. Bergeron N, Havel RJ (1996) Prolonged postprandial responses of lipids and apolipoproteins in triglyceride-rich lipoproteins of individuals expressing an apolipoprotein epsilon 4 allele. J Clin Invest 97:65–72

    Article  PubMed  CAS  Google Scholar 

  35. Cardona F, Morcillo S, Gonzalo-Marin M, Tinahones FJ (2005) The apolipoprotein E genotype predicts postprandial hypertriglyceridemia in patients with the metabolic syndrome. J Clin Endocrinol Metab 90:2972–2975

    Article  PubMed  CAS  Google Scholar 

  36. Stiefel P, Montilla C, Muniz-Grijalvo O et al (2001) Apolipoprotein E gene polymorphism is related to metabolic abnormalities, but does not influence erythrocyte membrane lipid composition or sodium-lithium countertransport activity in essential hypertension. Metabolism 50:157–160

    Article  PubMed  CAS  Google Scholar 

  37. de Knijff P, Boomsma DI, Feskens EJ et al (1994) Apolipoprotein E phenotype and blood pressure. Lancet 343:1234–1235

    Article  PubMed  Google Scholar 

  38. Uusitupa M, Sarkkinen E, Kervinen K, Kesaniemi YA (1994) Apolipoprotein E phenotype and blood pressure. Lancet 343:57

    Article  PubMed  CAS  Google Scholar 

  39. Yilmaz H, Isbir T, Agachan B, Aydin M (2001) Is epsilon4 allele of apolipoprotein E associated with more severe endorgan damage in essential hypertension? Cell Biochem Funct 19:191–195

    Article  PubMed  CAS  Google Scholar 

  40. Li X, Du Y, Du Y, Huang X (2003) Association of apolipoprotein E gene polymorphism with essential hypertension and its complications. Clin Exp Med 2:175–179

    Article  PubMed  CAS  Google Scholar 

  41. Paris D, Town T, Parker TA et al (1998) Isoform-specific vasoconstriction induced by apolipoprotein E and modulation of this effect by Alzheimer’s beta-amyloid peptide. Neurosci Lett 256:73–76

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit of Internal Medicine, Department of Clinical and Experimental Medicine, Cattedra di Medicina Interna, University of Verona, Policlinico Borgo Roma, 37134, Verona, Italy

    O. Olivieri, N. Martinelli, D. Girelli, F. Pizzolo, S. Friso & R. Corrocher

  2. Institute of Clinical Chemistry, University of Verona, Verona, Italy

    A. Bassi

  3. Section of Biology and Genetics, Department of Mother and Child and Biology — Genetics, University of Verona, Verona, Italy

    E. Trabetti & P. F. Pignatti

Authors
  1. O. Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Bassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Trabetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Girelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Pizzolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Friso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. F. Pignatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Corrocher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Olivieri.

Additional information

These authors contributed equally to the work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Olivieri, O., Martinelli, N., Bassi, A. et al. ApoE ε2/ε3/ε4 polymorphism, ApoC-III/ApoE ratio and metabolic syndrome. Clin. Exper.Med. 7, 164–172 (2007). https://doi.org/10.1007/s10238-007-0142-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-007-0142-y

Key words

Search

Navigation