Skip to main content
SpringerLink
Log in

Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans

  • Articles
  • Published:
Lipids

Abstract

Apolipoprotein E (apoE), an important determinant of plasma lipoprotein metabolism, has three common alleles (ε2, ε3, and ε4). Population studies have shown that the risk of diseases characterized by oxidative damage, such as coronary heart disease and Alzheimer’s disease, is significantly higher in ɛ4 carriers. We evaluated the association between apoE genotypes and plasma F2-isoprostane levels, an index of lipid peroxidation, in humans. Two hundred seventy-four healthy subjects (104 males, 170 females; 46.9±13.0 yr; 200 whites, 74 blacks; 81 nonsmokers, 64 passive smokers, and 129 active smokers) recruited for a randomized clinical antioxidant intervention trial were included in this analysis. ApoE genotype was determined by PCR and restriction enzyme digestion. Free plasma F2-isoprostane was measured by GC-MS. Genotype groups were compared using multiple regression analysis with adjustment for sex, age, race, smoking status, body mass index, plasma ascorbic acid, and β-carotene. Subjects with ε3/ε4 and ε4/ε4 genotype (ε4-carriers) and with ε2/ε3 and ε3/ε3 (non-ε4-carriers) were pooled for analysis. In subjects with high cholesterol levels (total cholesterol above 200 mg/dl), plasma F2-isoprostane levels were 29% higher in ε4 carriers than in non-ε4-carriers (P=0.0056). High-cholesterol subjects that are ε4 carriers have significantly higher levels of lipid peroxidation as assessed by circulating F2-isoprostane levels.

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

Abbreviations

AD:

Alzheimer’s disease

apoE:

apolipoprotein E

BMI:

body mass index

CHD:

coronary heart disease

CM:

chylomicrons

LDLC:

LDL cholesterol

OR:

odds ratio

References

  1. Wilson, P.W.F., Schaefer, E.J., Larson, M.G., and Ordovas, J.M. (1996) Apolipoprotein E Alleles and Risk of Coronary Disease, Arterioscler. Thromb. Vascular Biol. 16, 1250–1255.

    CAS  Google Scholar 

  2. Eichner, J.E., Dunn, S.T., Perveen, G., Thompson, D.M., Stewart, K.E., and Stroehla, B.C. (2002) Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review, Am. J. Epidemiol. 155, 487–495.

    Article  PubMed  Google Scholar 

  3. Gerdes, L.U., Gerdes, C., Kervinen, K., Savolainen, M., Klausen, I.C., Hansen, P.S., Kesaniemi, Y.A., and Faergeman, O. (2000) The Apolipoprotein ε4 Allele Determines Prognosis and the Effect on Prognosis of Simvastatin on Survivors of Myocardial Infarction: A Substudy of the Scandinavian Simvastatin Survival Study, Circulation 101, 1366–1371.

    PubMed  CAS  Google Scholar 

  4. Farrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., Myers, R.H., Pericak-Vance, M.A., and van Dujin, C.M. (1997) Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease. A Meta-analysis. ApoE and Alzheimer Disease Meta-analysis Consortium, JAMA 278, 1349–1356.

    Article  PubMed  CAS  Google Scholar 

  5. Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P., and Gauthier, S. (1993) Apolipoprotein E Polymorphism and Alzheimer’s Disease (1993), Lancet 342, 697–699.

    Article  PubMed  CAS  Google Scholar 

  6. Havel, J.H., and King, J.P. (1989) Lipoprotein and Lipid Metabolism Disorders. Introduction: Structure and Metabolism of Plasma Lipoproteins, in The Metabolic Basis of Inherited Disease (Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D., eds.) 6th edn., McGraw-Hill, New York, p. 1215.

    Google Scholar 

  7. Beisiegel, U., Weber, W., Ihrke, G., Herz, J., and Stanley, K.K. (1989) The LDL-Receptor-Related Protein, LRP, Is an Apolipoprotein E-Binding Protein, Nature 341, 162–164.

    Article  PubMed  CAS  Google Scholar 

  8. Mahley, R.W., and Rall, S.C., Jr. (2000) Apolipoprotein E: Far More Than a Lipid Transport Protein, Annu. Rev. Genomics Hum. Genetics 1, 507–537.

    Article  CAS  Google Scholar 

  9. Curtiss, L.K., and Boisvert, W.A. (2000) Apolipoprotein E and Atherosclerosis, Curr. Opin. Lipidol. 11, 243–251.

    Article  PubMed  CAS  Google Scholar 

  10. Lahoz, C., Schaefer, E.J., Cupples, A., Wilson, P.W.F., Levy, D., Osgood, D., Parpos, S., and Pedro-Botet, J. (2001) Apolipoprotein E Genotype and Cardiovascular Disease in the Framingham Heart Study, Atherosclerosis 154, 529–537.

    Article  PubMed  CAS  Google Scholar 

  11. Schiele, F., De Bacquer, D., Vincent-Viry, M., Beisiegel, U., Ehnholm, C., Evans, A., Kafatos, A., Martins, M.C., Sans, S., Sass, C., et al. (2000) The ApoEurope Group. Apolipoprotein E Serum Concentrations and Polymorphism in Six European Countries: The ApoEurope Project, Atherosclerosis 152, 475–488.

    Article  PubMed  CAS  Google Scholar 

  12. Welty, F.K., Lichtenstein, A.H., Barrett, P.H., Jenner, J.L., Dolnikowski, G.G., and Schaefer, E.J. (2000) Effects of ApoE Genotype on ApoB-48 and ApoB-100 Kinetics with Stable Isotopes in Humans, Arterioscler. Thromb. Vasc. Biol. 20, 1807–1810.

    PubMed  CAS  Google Scholar 

  13. Boerwinkle, E., and Sing, C.F. (1987) The Use of Measured Genotype Information in the Analysis of Quantitative Phenotypes in Man: II. The Role of the Apolipoprotein E Polymorphism in Determining Levels, Variability, and Covariability of Cholesterol, Betalipoprotein, and Triglycerides in a Sample of Unrelated Individuals, Am. J. Med. Genet. 27, 567–582.

    Article  PubMed  CAS  Google Scholar 

  14. Minihane, A.M., Khan, S., Leigh-Firbank, E.C., Talmud, P., Wright, J.W., Murphy, M.C., Griffin, B.A., and Williams, C.M. (2000) ApoE Polymorphism and Fish Oil Supplementation in Subjects with an Atherogenic Lipoprotein Phenotype, Arterioscler. Thromb. Vasc. Biol. 20, 1990–1997.

    PubMed  CAS  Google Scholar 

  15. Boer, J.M., Ehnholm, C., Menzel, H.J., Havekes, L.M., Rosseneu, M., O’Reilly, D.S., and Tiret, L. (1997) Interactions Between Lifestyle-Related Factors and the ApoE Polymorphism on Plasma Lipids and Apolipoproteins. The EARS Study. European Atherosclerosis Research Study, Arterioscler. Thromb. Vas. Biol. 17, 1675–1681.

    CAS  Google Scholar 

  16. Halliwell, B., and Gutteridge, J.M. (1990) Free Radicals in Biology and Medicine, Clarendon Press, Oxford, United Kingdom.

    Google Scholar 

  17. Christen, Y. (2000) Oxidative Stress and Alzheimer Disease, Am. J. Clin. Nutr. 71, 621S-629S.

    PubMed  CAS  Google Scholar 

  18. Halliwell, B. (1994) Free Radicals and Antioxidants: A Personal View, Nutr. Rev. 1, 253–265.

    Google Scholar 

  19. Schippling, S., Kontush, A., Arlt, S., Buhmann, C., Sturenburg, H.J., Mann, U., Muler-Thomsen, T., and Beisiegel, U. (2000) Increased Lipoprotein Oxidation in Alzheimer’s Disease, Free Radic. Biol. Med. 28, 351–360.

    Article  PubMed  CAS  Google Scholar 

  20. Jolivalt, C., Leininger-Muller, B., Bertrand, P., Herber, R., Christen, Y., and Siest, G. (2000) Differential Oxidation of Apolipoprotein E Isoforms and Interaction with Phospholipids, Free Radic. Biol. Med. 28, 129–140.

    Article  PubMed  CAS  Google Scholar 

  21. Miyata, M., and Smith, J.D. (1996) Apolipoprotein E Allele-Specific Antioxidant Activity and Effects on Cytotoxicity by Oxidative Insults and β-Amyloid Peptides, Nat. Genet. 14, 55–61.

    Article  PubMed  CAS  Google Scholar 

  22. Pratico, D., Rokach, J., and Tangirala, R.K. (1999) Brains of Aged Apolipoprotein E-Deficient Mice Have Increased Levels of F2-Isoprostanes, in vivo Markers of Lipid Peroxidation, J. Neurochem. 73, 736–741.

    Article  PubMed  CAS  Google Scholar 

  23. Ramassamy, C., Averill, D., Beffert, U., Bastianetto, S., Theroux, L., Lussier-Cacan, S., Cohn, J.S., Christen, Y., Davignon, J., et al. (1999) Oxidative Damage and Protection by Antioxidants in the Frontal Cortex of Alzheimer’s Disease Is Related to the Apolipoprotein E Genotype, Free Radic. Biol. Med. 27, 544–553.

    Article  PubMed  CAS  Google Scholar 

  24. Dietrich, M., Block, G., Hudes, M., Morrow, J.D., Norkus, E.P., Traber, M.G., Cross, C.E., and Packer, L. (2002) Antioxidant Supplementation Decreases F(2)-Isoprostanes in Plasma of Smokers, Cancer Epidemiol. Biomarkers Prev. 11, 7–13.

    PubMed  CAS  Google Scholar 

  25. Dietrich, M., Block, G., Benowitz, N.L., Morrow, J.D., Hudes, M., Jacob, P., III, Norkus, E.P., and Packer, L. (2003) Vitamin C Supplementation Decreases Oxidative Stress Biomarker F2-Isoprostanes in Plasma of Nonsmokers Exposed to Environmental Tobacco Smoke, Nutr. Cancer 45, 176–184.

    Article  PubMed  CAS  Google Scholar 

  26. Morrow, J.D., and Roberts, L.J., II (1999) Mass Spectrometric Quantification of F2-Isoprostanes in Biological Fluids and Tissues as Measure of Oxidant Stress, Methods Enzymol. 300, 3–12.

    Article  PubMed  CAS  Google Scholar 

  27. Sowell, A.L., Huff, D.L., Yeager, P.R., Caudill, S.P., and Gunter, E.W. (1994) Retinol, α-Tocopherol, Lutein/Zeaxanthin, β-Cryptoxanthin, Lycopene, α-Carotene, trans-β-Carotene, and Four Retinyl Esters in Serum Determined Simultaneously by Reversed-Phase HPLC with Multiwavelength Detection, Clin. Chem. 40, 411–416.

    PubMed  CAS  Google Scholar 

  28. Otles, S. (1995) Comparative Determination of Ascorbic Acid in Bass (Morone lebrax) Liver by HPLC and DNPH Methods, Int. J. Food Sci. Nutr. 46, 229–232.

    PubMed  CAS  Google Scholar 

  29. Jacob, P.I., Wilson, M., and Benowitz N.L. (1981) Improved Gas Chromatographic Method for the Determination of Nicotine and Cotinine in Biologic Fluids, J. Chromatogr. 222, 61–70.

    PubMed  CAS  Google Scholar 

  30. Jacob, P.I., Yu, L., Wilson, M., and Benowitz, N.L. (1991) Selected Ion Monitoring Method for Determination of Nicotine, Cotinine and Deuterium-Labeled Analogs: Absence of an Isotope Effect in the Clearance of (S)-Nicotine-3′,3′-d2 in Humans, Biol. Mass Spectrom. 20, 247–252.

    Article  PubMed  CAS  Google Scholar 

  31. Block, G., Dietrich, M., Norkus, E.P., Morrow, J.D., Hudes, M., Caan, B., and Packer, L. (2002) Factors Associated with Oxidative Stress in Human Populations, Am. J. Epidemiol. 156, 274–285.

    Article  PubMed  Google Scholar 

  32. Mazzone, T. (1996) Apolipoprotein E Secretion by Macrophages: Its Potential Physiological Functions, Curr. Opin. Lipidol. 14, 55–61.

    Google Scholar 

  33. Patrono, C., and Fitzgerald, G.A. (1997) Isoprostanes: Potential Markers of Oxidative Stress in Atherothrombotic Disease, Arterioscler. Thromb. Vasc. Biol. 17, 2309–2315.

    PubMed  CAS  Google Scholar 

  34. Ide, T., Hsutsui, H., Ohashi, N., Hayashidani, S., Suematsu, N., Tschihashi, M., Tamai, H., and Takeshita, A. (2002) Greater Oxidative Stress in Healthy Young Men Compared with Premenopausal Women, Arterioscler. Thromb Vasc. Biol. 22, 438–442.

    Article  PubMed  CAS  Google Scholar 

  35. Morrow, J.D., Frei, B., Longmire, A.W., Gaziano, J.M., Lynch, S.M., Shyr, Y., Strauss, W.E., Oates, J.A., and Roberts, L.J., II (1995) Increase in Circulating Products of Lipid Peroxidation (F2-isoprostanes) in Smokers: Smoking as a Cause of Oxidative Damage, New Engl. J. Med. 332, 1198–1203.

    Article  PubMed  CAS  Google Scholar 

  36. Chehne, F., Oguogho, A., Lupattelli, G., Budinsky, A.C., Palumbo, B., and Sinzinger, H. (2001) Increase of Isoprostane 8-Epi-PGF(2α) After Restarting Smoking, Prostaglandins Leukot. Essent. Fatty Acids. 64, 307–310.

    Article  PubMed  CAS  Google Scholar 

  37. Davi, G., Alessandrini, P., Mezzetti, A., Minotti, G., Bucciarelli, T., Costantini, F., Cipollone, F., Bon, G.B., Ciabattoni, G., and Patrono, C. (1999) In vivo Formation of 8-Iso-prostaglandin F2α and Platelet Activation in Diabetes Mellitus: Effects of Improved Metabolic Control and Vitamin E Supplementation, Circulation 99, 224–229.

    PubMed  CAS  Google Scholar 

  38. Reilly, M.P., Pratico, D., Delanty, N., DiMinno, G., Tremoli, E., Rader, D., Kapoor, S., Rokach, J., Lawson, J., and FitzGerald, G.A. (1998) Increased Formation of Distinct F2-Isoprostanes in Hypercholesterolemia, Circulation 98, 2822–2828.

    PubMed  CAS  Google Scholar 

  39. Davi, G., Alessandrini, P., Mezzetti, A., Minotti, G., Bucciarelli, T., Costantini, F., Cipollone, F., Bon, G.B., Ciabattoni, G., and Patrono, C. (1997) In vivo Formation of 8-Epi-prostaglandin F2 Is Increased in Hypercholesterolemia, Arterioscler. Thromb. Vasc. Biol. 17, 3230–3235.

    PubMed  CAS  Google Scholar 

  40. Mayne, S.T., Walter, M., Cartmel, B., Goodwin, W.J., Jr., and Blumberg, J. (2004) Supplemental β-Carotene, Smoking and Urinary F2-Isoprostane Excretion in Patients with Prior Early Stage Head and Neck Cancer, Nutr. Cancer 49, 1–6.

    Article  PubMed  CAS  Google Scholar 

  41. Wendland, B.E., Aghdassi, E., Tam, C., Carrier, J., Steinhart, A.H., Wolman, S.L., Baron, D., and Allard, J.P. (2001) Lipid Peroxidation and Plasma Antioxidant Micronutrients in Crohn Disease, Am. J. Clin. Nutr. 74, 259–264.

    PubMed  CAS  Google Scholar 

  42. Aghdassi, E., and Allard, J.P. (2000) Breath Alkanes as a Marker of Oxidative Stress in Different Clinical Conditions, Free Radic. Biol. Med. 28, 880–886.

    Article  PubMed  CAS  Google Scholar 

  43. Humphries, S.E., Talmud, P.J., Hawe, E., Bolla, M., Day, I.N.M., and Miller, G.J. (2001) Apolipoprotein ε4 and Coronary Heart Disease in Middle-Aged Men Who Smoke: A Prospective Study, Lancet 358, 115–119.

    Article  PubMed  CAS  Google Scholar 

  44. Morrow, J.A., Segall, M.L., Lund-Katz, S., Phillips, M.C., Knapp, M., Rupp, B., and Weisgraber, K.H. (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 

  45. Dong, L.M., and Weisgraber, K.H. (1996) Human Apolipoprotein ε4 Domain Interaction. Arginine 61 and Glutamic Acid 255 Interact to Direct the Preference for Very Low Density Lipoproteins, J. Biol. Chem. 271, 19053–19057.

    Article  PubMed  CAS  Google Scholar 

  46. Regan, L. (1995) Protein Design: Novel Metal Binding Sites, Trends Biochem. Sci. 20, 280–285.

    Article  PubMed  CAS  Google Scholar 

  47. Wilson, C., Wardell, M.R., Weisgraber, K.H., Mahley, R.W., and Agard, D.A. (1991) Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E, Science 252, 1817–1822.

    Article  PubMed  CAS  Google Scholar 

  48. Levine, R.L., Mosini, L., Berlett, B.S., and Stadtman, E.R. (1996) Methionine Residues as Endogenous Antioxidants in Proteins, Proc. Nat. Acad. Sci. 93, 15036–15040.

    Article  PubMed  CAS  Google Scholar 

  49. Garner, B., Waldeck, A.R., Witting, P.K., Rye, K.A., and Stocker, R. (1998) Oxidation of High Density Lipoproteins. II. Evidence for Direct Reduction of Lipid Hydroperoxides by Methionine Residues of Apolipoprotein A1 and AII, J. Biol. Chem. 273, 6088–6095.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Public Health, University of California, Berkeley, California

    Marion Dietrich, Youqing Hu & Gladys Block

  2. Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California

    Lester Packer

  3. Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee

    Jason D. Morrow

  4. Department of Nutritional Sciences, University of California, Berkeley, California

    Mark Hudes

  5. Institute of Human Nutrition and Food Science, Christian Albrechts University, Kiel, Germany

    Gerald Rimbach

  6. Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, RG6 6AP, Reading, UK

    Estibaliz Olano, Gulbahar Abdukeyum & Anne M. Minihane

Authors
  1. Marion Dietrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Youqing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gladys Block
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Estibaliz Olano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lester Packer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jason D. Morrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Hudes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gulbahar Abdukeyum
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerald Rimbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anne M. Minihane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne M. Minihane.

About this article

Cite this article

Dietrich, M., Hu, Y., Block, G. et al. Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans. Lipids 40, 329–334 (2005). https://doi.org/10.1007/s11745-006-1390-4

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-006-1390-4

Keywords

Search

Navigation