Advertisement

Irish Journal of Medical Science

, Volume 177, Issue 1, pp 29–33 | Cite as

Apolipoprotein E promoter polymorphisms (−491A/T and −427T/C) and Alzheimer’s disease: no evidence of association in the Irish population

  • C. A. Lynch
  • J. Brazil
  • B. Cullen
  • D. Coakley
  • M. Gill
  • B. A. Lawlor
  • Z. Hawi
Original Article

Abstract

Background

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder with as yet poorly understood aetiology. Both environmental and genetic factors have been implicated as predisposing factors. The APOE e4 allele is an established genetic susceptibility factor for AD for several populations including the Irish. Polymorphisms (−491A/T and −427T/C) at the promoter region of the APOE gene are postulated to affect the expression of the gene through differential binding of transcription factors.

Aims

Two APOE promoter polymorphisms (−491A/T and −427T/C) are examined for possible association with AD.

Methods

Using a case-control study design, a sample of 112 Irish late onset Alzheimer’s (LOAD) patients and 107 ethnically matched controls were investigated for association with the above polymorphisms.

Conclusions

No evidence of association between any of the examined markers and AD was observed. Haplotype analysis using markers −491A/T and −427T/C in conjunction with the APOE (Hha I) polymorphism revealed significant associations of three haplotypes with AD. However, this association was mainly due to the highly significant association of the APOE e4 allele with AD and not of the promoter variants.

Keywords

Alzheimer’s disease Apolipoprotein E Promoter polymorphisms 

Notes

Acknowledgments

We would like to acknowledge the Mercer Foundation, the Medical Research Council (UK), the Health Research Board and the Higher Education Authority for financial support.

References

  1. 1.
    Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, Frey W 2nd, Haase AT (1991) Neuropathological changes in scrapie and Alzheimer’s disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol 65(9):4759–4768PubMedGoogle Scholar
  2. 2.
    Corder E, Saunders A, Strittmatter W, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Genetic dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923PubMedCrossRefGoogle Scholar
  3. 3.
    Saunders A, Strittmatter W, Schmechael D, George-Hyslop P, Perick-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-Maclachlan DR, Alberts MJ et al (1993) Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s Disease. Neurology 43:1467–1472PubMedGoogle Scholar
  4. 4.
    Levy-Lahad E, Lahad A, Wijsman EM, Bird TD, Schellenberg GD (1995) Apolipoprotein E genotypes and age of onset in early-onset familial Alzheimer’s disease. Ann Neurol 38:678–680PubMedCrossRefGoogle Scholar
  5. 5.
    Hawi Z, Sheehan K, Lynch A, Evans I, Lowe N, Lawlor B, Gill M (2003) Late onset Alzheimer disease and apolipoprotein E (APOE) association in the Irish population: relative risk and attributable fraction. Ir J Med Sci 172 (2):74–76PubMedCrossRefGoogle Scholar
  6. 6.
    Artiga MJ, Bullido MJ, Frank A, Sastre I, Receuro M, Garcia MA, Lendon CL, Han SW, Morris JC, Vasquez J, Goate A, Valdiviesco F (1998) Risk for Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet 7(12):1887–1892PubMedCrossRefGoogle Scholar
  7. 7.
    Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J, Lendon C, Han SW, Morris JC, Frank A, Vazquez J, Goate A, Valdivieso F (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer’s dementia. Nat Genet 18:69–71PubMedCrossRefGoogle Scholar
  8. 8.
    McKhann G, Drachman DM, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS/ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  9. 9.
    Laws SM, Hone E, Taddei K, Harper C, Dean B, McClean C, Masters C, Lautenschlager N, Gandy SE, Martins RN (2002) Variation at the APOE −491-promoter locus is associated with altered brain levels of apolipoprotein E. Mol Psychiatry 7(8):886–890PubMedCrossRefGoogle Scholar
  10. 10.
    Zhao JH, Sham PC (2002) Faster allelic association analysis using unrelated subjects. Hum Hered 53(1):36–41PubMedCrossRefGoogle Scholar
  11. 11.
    Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE, Christensen H, Croft L, Jacomb PA (1995) Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet 346:1387–1390PubMedCrossRefGoogle Scholar
  12. 12.
    Bennett C, Crawford F, Osborne A, Diaz P, Hoyne J, Lopez R, Roq Duara R, Rossor M, Mullan M (1995) Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer’s disease but is not causative. Am J Hum Genet 60(1):1–6Google Scholar
  13. 13.
    Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J, Vazquez J, Valdivieso F (1998) Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett 421(2):105–108PubMedCrossRefGoogle Scholar
  14. 14.
    Roks G, Cruts M, Bullido MJ, Backhovens H, Artiga MJ, Hofman A, Valdivieso F, Van Brockhoven C, Van Duijn C (1998) The −491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early onset Alzheimer’s disease. Neurosci Lett 258:65–68PubMedCrossRefGoogle Scholar
  15. 15.
    Roks G, Houwing-Duistermaat JJ, Dermaut B, Serneels S, Havekes LM, Hofman A, Breteler MMB, Van Broeckhoven C, Van Duijn CM (2002) Effect of the APOE −491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer’s disease: the Rotterdam Study. Am J Med Genet 114:570–573PubMedCrossRefGoogle Scholar
  16. 16.
    Zurutuza L, Verpillat P, Raux G, Hannequin D, Puel M, Belliard S, Michon A, Pothin Y, Camuzat A, Penet C, Martin C, Brice A, Campion D, Clerget-Darpoux F, Frebourg T (2000) APOE promoter polymorphisms do not confer independent risk for Alzheimer’s disease in a French population. Eur J Hum Genet 8(9):713–716PubMedCrossRefGoogle Scholar
  17. 17.
    Wang JC, Kwon MD, Shah P, Morris JC, Goate A (2000) Effect of APOE genotype and promoter polymorphism on risk of Alzheimer’s disease. Neurology 55:1644–1649PubMedGoogle Scholar
  18. 18.
    Lambert JC, Berr C, Pasquier F, Delacourte A, Frigard B, Cottel D, Perez-Tur J, Mouroux V, Mohr M, Cecyre D, Galasko D, Lendon C, Poirier J, Hardy J, Mann D, Amouyel P, Chartier-Harlin MC (1998) Pronounced impact of Th1/E47cs mutation compared with −491 AT mutation on neural APOE gene expression and risk of developing Alzheimer’s disease. Hum Mol Genet 7(9):1511–1516PubMedCrossRefGoogle Scholar
  19. 19.
    Bullido MJ, Valdiviesco F (2000) Apolipoprotein E gene promoter polymorphisms in Alzheimer’s disease. Microsc Res Tech 50(4):261–267PubMedCrossRefGoogle Scholar
  20. 20.
    Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA (2001) Haplotype tagging for the identification of common disease genes. Nat Genet 29(2):233–237PubMedCrossRefGoogle Scholar
  21. 21.
    Town T, Paris D, Fallin D, Duara R, Barker W, Gold M, Crawford F, Mullan M (1998) The −491 A/T apolipoprotein E promoter polymorphism association with Alzheimer’s disease: independent risk and linkage disequilibrium with the known APOE polymorphism. Neurosci Lett 252:95–98PubMedCrossRefGoogle Scholar

Copyright information

© Royal Academy of Medicine in Ireland 2007

Authors and Affiliations

  • C. A. Lynch
    • 1
  • J. Brazil
    • 2
  • B. Cullen
    • 1
  • D. Coakley
    • 1
  • M. Gill
    • 2
  • B. A. Lawlor
    • 1
  • Z. Hawi
    • 2
  1. 1.Mercer’s Institute for Research on Ageing, Hospital 4St James’s HospitalDublin 8Ireland
  2. 2.Department of Genetics and PsychiatryTrinity CollegeDublin 2Ireland

Personalised recommendations