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Apolipoprotein E ε4 Genotype is Independently Associated with Increased Intima-Media Thickness in a Recessive Pattern

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Lipids

Abstract

Polymorphisms in the apolipoprotein E (Apo E) gene have been associated with lipid levels, carotid intima media thickness (CCA-IMT), inflammation and cardiovascular disease (CVD). Earlier findings suggested an association of the Apo E alleles with increased CCA-IMT following a recessive pattern. Whether associations might be independent of C-reactive protein (CRP), lipid levels and other CVD risk factors is not known. We investigated the relationships between Apo E (ε2, ε3 and ε4 alleles) and CCA-IMT, measured by B-mode ultrasound, in dominant and recessive models in a community-based sample of 437 men 75 years of age. In men homozygous for the ε4 allele CCA-IMT was significantly increased by 0.13 mm to 0.86 ± 0.16 mm compared to 0.73 ± 0.19 mm in non- ε4-carriers (P = 0.0012) and 0.73 ± 0.21 mm in ε4 heterozygous (P = 0.0044) in unadjusted recessive models. The association between Apo E ε4 genotype and CCA-IMT was independent of Apo E ε2 and Apo E ε3 alleles, CRP, lipid variables (TG, LDL, HDL) and other CVD risk factors (smoking, hypertension, body mass index, diabetes) (P = 0.018). No relations between Apo E genotype and CCA-IMT were observed in dominant models. No significant associations between the Apo E ε2 and ε3 alleles and CCA-IMT were found. In this study, men homozygous with the ApoE ε4 allele had thicker CCA-IMT, independently of Apo E ε2 and ε3 alleles, CRP, lipid variables (TG, LDL, HDL) and other CVD risk factors (smoking, hypertension, body mass index, diabetes), suggesting CCA-IMT to be modified by the ApoE ε4 genotype in a recessive pattern.

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References

  1. Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM (2002) A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiovasc Res 54(3):528–538

    Article  PubMed  CAS  Google Scholar 

  2. Hanlon CS, Rubinsztein DC (1995) Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans. Atherosclerosis 112(1):85–90

    Article  PubMed  CAS  Google Scholar 

  3. 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 

  4. Elosua R, Ordovas JM, Cupples LA, Fox CS, Polak JF, Wolf PA et al (2004) Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study. J Lipid Res 45(10):1868–1875 Epub 2004 Jul 16

    Article  PubMed  CAS  Google Scholar 

  5. Beilby JP, Hunt CC, Palmer LJ, Chapman CM, Burley JP, McQuillan BM et al (2003) Apolipoprotein E gene polymorphisms are associated with carotid plaque formation but not with intima-media wall thickening: results from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Stroke 34(4):869–874 Epub 2003 Mar 13

    Article  PubMed  CAS  Google Scholar 

  6. Karvonen J, Kauma H, Kervinen K, Ukkola O, Rantala M, Paivansalo M et al (2002) Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J Hypertens 20(12):2371–2378

    Article  PubMed  CAS  Google Scholar 

  7. Haraki T, Takegoshi T, Kitoh C, Wakasugi T, Saga T, Hirai JI et al (2002) Carotid artery intima-media thickness and brachial artery flow-mediated vasodilation in asymptomatic Japanese male subjects amongst apolipoprotein E phenotypes. J Intern Med 252(2):114–120

    Article  PubMed  CAS  Google Scholar 

  8. Djousse L, Myers RH, Province MA, Hunt SC, Eckfeldt JH, Evans G et al (2002) Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis: National Heart, Lung, and Blood Institute Family Heart Study. Stroke 33(5):1357–1361

    Article  PubMed  Google Scholar 

  9. Slooter AJ, Bots ML, Havekes LM, del Sol AI, Cruts M, Grobbee DE et al (2001) Apolipoprotein E and carotid artery atherosclerosis: the Rotterdam study. Stroke 32(9):1947–1952

    PubMed  CAS  Google Scholar 

  10. Ilveskoski E, Loimaala A, Mercuri MF, Lehtimaki T, Pasanen M, Nenonen A et al (2000) Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men. Atherosclerosis 153(1):147–153

    Article  PubMed  CAS  Google Scholar 

  11. Horejsi B, Spacil J, Ceska R, Vrablik M, Haas T, Horinek A (2000) The independent correlation of the impact of lipoprotein(a) levels and apolipoprotein E polymorphism on carotid artery intima thickness. Int Angiol 19(4):331–336

    PubMed  CAS  Google Scholar 

  12. Hanon O, Girerd X, Luong V, Jeunemaitre X, Laurent S, Safar ME (2000) Association between the apolipoprotein E polymorphism and arterial wall thickness in asymptomatic adults. J Hypertens 18(4):431–436

    Article  PubMed  CAS  Google Scholar 

  13. Zannad F, Visvikis S, Gueguen R, Sass C, Chapet O, Herbeth B et al (1998) Genetics strongly determines the wall thickness of the left and right carotid arteries. Hum Genet 103(2):183–188

    Article  PubMed  CAS  Google Scholar 

  14. Sass C, Zannad F, Herbeth B, Salah D, Chapet O, Siest G et al (1998) Apolipoprotein E4, lipoprotein lipase C447 and angiotensin-I converting enzyme deletion alleles were not associated with increased wall thickness of carotid and femoral arteries in healthy subjects from the Stanislas cohort. Atherosclerosis 140(1):89–95

    Article  PubMed  CAS  Google Scholar 

  15. Kogawa K, Nishizawa Y, Hosoi M, Kawagishi T, Maekawa K, Shoji T et al (1997) Effect of polymorphism of apolipoprotein E and angiotensin-converting enzyme genes on arterial wall thickness. Diabetes 46(4):682–687

    Article  PubMed  CAS  Google Scholar 

  16. Vauhkonen I, Niskanen L, Ryynanen M, Voutilainen R, Partanen J, Toyry J et al (1997) Divergent association of apolipoprotein E polymorphism with vascular disease in patients with NIDDM and control subjects. Diabet Med 14(9):748–756

    Article  PubMed  CAS  Google Scholar 

  17. Cattin L, Fisicaro M, Tonizzo M, Valenti M, Danek GM, Fonda M et al (1997) Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. Arterioscler Thromb Vasc Biol 17(1):91–94

    PubMed  CAS  Google Scholar 

  18. Terry JG, Howard G, Mercuri M, Bond MG, Crouse JR 3rd (1996) Apolipoprotein E polymorphism is associated with segment-specific extracranial carotid artery intima-media thickening. Stroke 27(10):1755–1759

    PubMed  CAS  Google Scholar 

  19. de Andrade M, Thandi I, Brown S, Gotto A Jr, Patsch W, Boerwinkle E (1995) Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet 56(6):1379–1390

    PubMed  Google Scholar 

  20. Volcik KA, Barkley RA, Hutchinson RG, Mosley TH, Heiss G, Sharrett AR et al (2006) Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thickness but not incident coronary heart disease in 12,491 ARIC study participants. Am J Epidemiol 164(4):342–348

    Article  PubMed  Google Scholar 

  21. Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF (1995) Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 91(2):265–269

    PubMed  CAS  Google Scholar 

  22. Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8(1):1–21

    PubMed  CAS  Google Scholar 

  23. Wohlin M, Sundstrom J, Arnlov J, Andren B, Zethelius B, Lind L (2003) Impaired insulin sensitivity is an independent predictor of common carotid intima-media thickness in a population sample of elderly men. Atherosclerosis 170(1):181–185

    Article  PubMed  CAS  Google Scholar 

  24. Sundstrom J, Lind L, Nystrom N, Zethelius B, Andren B, Hales CN et al (2000) Left ventricular concentric remodeling rather than left ventricular hypertrophy is related to the insulin resistance syndrome in elderly men. Circulation 101(22):2595–2600

    PubMed  CAS  Google Scholar 

  25. Wikstrand J, Wendelhag I (1994) Methodological considerations of ultrasound investigation of intima- media thickness and lumen diameter. J Intern Med 236(5):555–559

    Article  PubMed  CAS  Google Scholar 

  26. Hsu TM, Chen X, Duan S, Miller RD, Kwok PY (2001) Universal SNP genotyping assay with fluorescence polarization detection. Biotechniques 31(3):560, 562, 564–568 passim

    Google Scholar 

  27. Salonen JT, Salonen R (1993) Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation 87(3 Suppl):II56–II65

    PubMed  CAS  Google Scholar 

  28. Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37(2):268–285

    PubMed  CAS  Google Scholar 

  29. Takahashi S, Sakai J, Fujino T, Miyamori I, Yamamoto TT (2003) The very low density lipoprotein (VLDL) receptor—a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues. Mol Cell Biochem 248(1–2):121–127

    Article  PubMed  CAS  Google Scholar 

  30. Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W et al (2000) Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem 275(33):25616–25624

    Article  PubMed  CAS  Google Scholar 

  31. Mahley RW, Huang Y, Weisgraber KH (2006) Putting cholesterol in its place: apoE and reverse cholesterol transport. J Clin Invest 116(5):1226–1229

    Article  PubMed  CAS  Google Scholar 

  32. Bellosta S, Mahley RW, Sanan DA, Murata J, Newland DL, Taylor JM et al (1995) Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. J Clin Invest 96(5):2170–2179

    Article  PubMed  CAS  Google Scholar 

  33. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA et al (1997) Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci USA 94(9):4647–4652

    Article  PubMed  CAS  Google Scholar 

  34. Huang Y, Liu XQ, Rall SC Jr, Taylor JM, von Eckardstein A, Assmann G et al (1998) Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem 273(41):26388–26393

    Article  PubMed  CAS  Google Scholar 

  35. van Dijk KW, van Vlijmen BJ, van’t Hof HB, van der Zee A, Santamarina-Fojo S, van Berkel TJ et al (1999) In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE. J Lipid Res 40(2):336–344

    PubMed  Google Scholar 

  36. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347(20):1557–1565

    Article  PubMed  CAS  Google Scholar 

  37. Persson L, Boren J, Nicoletti A, Hansson GK, Pekna M (2005) Immunoglobulin treatment reduces atherosclerosis in apolipoprotein E low-density lipoprotein receptor mice via the complement system. Clin Exp Immunol 142(3):441–445

    PubMed  CAS  Google Scholar 

  38. Marz W, Scharnagl H, Hoffmann MM, Boehm BO, Winkelmann BR (2004) The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study). Eur Heart J 25(23):2109–2119

    Article  PubMed  CAS  Google Scholar 

  39. Albert MA, Danielson E, Rifai N, Ridker PM (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286(1):64–70

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The SNPs were genotyped by the Wallenberg Consortium North (WCN) SNP technology platform. We thank Kristina Larsson for performing the genotyping assays. We thank the Swedish Heart and Lung Foundation for their support.

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Authors and Affiliations

  1. Department of Public Health and Caring Sciences/Geriatrics and Clinical Nutrition, Faculty of Medicine, Uppsala University, Uppsala Science Park, 751 85, Uppsala, Sweden

    M. Wohlin, Lars Lannfelt & S. Basu

  2. Medical Sciences, Uppsala University, Uppsala, Sweden

    J. Sundström, Tomas Axelsson, A. C. Syvänen, B. Andrén & L. Lind

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  1. M. Wohlin
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  2. J. Sundström
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Correspondence to M. Wohlin.

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Wohlin, M., Sundström, J., Lannfelt, L. et al. Apolipoprotein E ε4 Genotype is Independently Associated with Increased Intima-Media Thickness in a Recessive Pattern. Lipids 42, 451–456 (2007). https://doi.org/10.1007/s11745-007-3045-5

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  • DOI: https://doi.org/10.1007/s11745-007-3045-5

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