Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease

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Abstract

A specific isoform of apolipoprotein E has been associated with the accelerated rate of disease expression of sporadic Alzheimer's disease (AD) and late-onset familial AD (FAD)1–12. An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APR) gene (APP717 and APP670/671)13 carrying the APOEɛ-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations14, or in chromosome 14-linked familial AD patients15.Hypothesizing that receptors for apoE-containing lipoprotein16–22 act as a potential risk factor for AD, we performed an association study using a polymorphic triplet (CGG) repeat21,23 in the gene for the VLDL receptor (VLDL-R), a receptor for apoE-containing lipoproteins.The frequency of the 5-repeat allele was significantly higher in all of the Japanese sporadic AD patients (P<0.02) than in the Japanese controls. Moreover, the odds ratio was significantly increased in the AD patients homozygous for the 5-repeat allele (OR=2.1,95% Cl=[1.1–4.2]). Multiple logistic regression analysis reveals that the relative risk conferred by the presence of two copies of the 5-repeat allele and at least one copy of the APOEɛ-4 allele is 8.7 (95% Cl=[2.9–25.8]). Our results suggest that the VLDL-R gene is a susceptibility gene for AD.

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References

  1. 1

    Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

  2. 2

    Saunders, A.M. et al. Association of apolipoprotein E allele ɛ4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472 (1993).

  3. 3

    Strittmatter, W.J. et al. Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. natn. Acad. Sci. U.S.A. 90, 1977–1981 (1993).

  4. 4

    Borgaonkar, D.S., Schmidt, L.C., Martin, S.E. & Kanzer, M.D. Linkage of late-onset Alzheimer's disease with apolipoprotein E type 4 on chromosome 19. Lancet 342, 625 (1993).

  5. 5

    Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P. & Gauthier, S. E polymorphism and Alzheimer's disease. Lancet 342, 697–699 (1993).

  6. 6

    Saunders, A.M. et al. Apolipoprotein E e4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet 342, 710–711 (1993).

  7. 7

    Payami, H., Kaye, J., Heston, L.L., Bird, T.D. & Schellenberg, G.D. Apolipoprotein E genotype and Alzheimer's disease. Lancet 342, 738 (1993).

  8. 8

    Ueki, A., Kawano, M., Namba, Y., Kawakami, M. & Ikeda, K. A high frequency of apolipoprotein E4 isoprotein in Japanese patients with late-onset nonfamilial Alzheimer's disease. Neurosci. Lett. 163, 166–168 (1993).

  9. 9

    Rebeck, G.W., Reiter, J.S., Strickland, O.K. & Hyman, B.T. Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions. Neuron 11, 575–580 (1993).

  10. 10

    Okuizumi, K. et al. APOE-e4 and early-onset Alzheimer's disease. Nature Genet. 7, 10–11 (1994).

  11. 11

    van Duijn, C.M. et al. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nature Genet. 7, 74–78 (1994).

  12. 12

    Chartier-Harlin, M.C. et al. Apolipoprotein E, ɛ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum. molec. Genet. 3, 569–574 (1994).

  13. 13

    Hardy, J. et al. Apolipoprotein E genotype and Alzheimer's disease. Lancet 342, 737–738 (1993).

  14. 14

    Haan, J. et al. The apolipoprotein E e4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations. Ann. Neurol. 36, 434–437 (1994).

  15. 15

    Van Broeckhoven, C. et al. APOE genotype does not modulate model age of onset in families with chromosome 14-encoded Alzheimer's disease. Neurosci. Lett. 169, 179–180 (1994).

  16. 16

    Mahley, R.W. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988).

  17. 17

    Kowal, R.C., Herz, J., Goldstein, J.L., Esser, V. & Brown, M.S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc. natn. Acad. Sci. U.S.A. 86, 5810–5814 (1989).

  18. 18

    Beisiegel, U., Weber, W., Ihrke, G., Herz, J. & Stanley, K.K. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 341, 162–164 (1989).

  19. 19

    Strickland, D.K. et al. Sequence identity between the α2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J. biol. Chem. 265, 17401–17404 (1990).

  20. 20

    Takahashi, S., Kawarabayashi, Y., Nakai, T., Sakai, J. & Yamamoto, T. Rabit very low density lipoprotein receptor: A low density lipoprotein receptor-like protein with distinct ligand specificity. Proc. natn. Acad. Sci. U.S.A. 89, 9252–9256 (1992).

  21. 21

    Sakai, J. et al. Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene. J. biol. Chem. 269, 73–2182 (1994).

  22. 22

    Yamamoto, T., Takahashi, S., Sakai, J. & Kawarabayashi, Y. The very low density lipoprotein receptor. A second lipoprotein receptor that may mediate uptake of fatty acids into muscle and fat cells. Trends Cardiovasc. Med. 3, 144–148 (1993).

  23. 23

    Jokinen, E., Sakai, J., Yamamoto, T. & Hobbs, H.H. CGG triple repeat polymorphism in VLDL receptor (VLDL-R) gene. Hum. molec. Genet. 3, 521 (1994).

  24. 24

    Mantel, N. & Haenszel, W. Statistical aspects on the analysis of data from retrospective studies of disease. J. natn. Cancer Inst. 22, 719–748 (1959).

  25. 25

    SAS Technical Report P-200. Release 6.04, 175–230 (SAS Institutes, Gary, 1991).

  26. 26

    SAS Technical Report P229. Release 6.07, 243–248 (SAS Institutes, Gary, 1992).

  27. 27

    Khachaturian, Z.S. Diagnosis of Alzheimer's disease. Arch.Neurol. 42, 1097–1105 (1985).

  28. 28

    McKahnn, G. et al. 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, 939–944 (1984).

  29. 29

    Wenham, P.R., Price, W.H. & Blundell, G. Apolipoprotein E genotyping by one-stage PCR. Lancet 337, 1158–1159 (1991).

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Okuizumi, K., Onodera, O., Namba, Y. et al. Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease. Nat Genet 11, 207–209 (1995) doi:10.1038/ng1095-207

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