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. 2003 Jun;40(6):424–430. doi: 10.1136/jmg.40.6.424

Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease

J Lambert 1, E Luedecking-Zimmer 1, S Merrot 1, A Hayes 1, U Thaker 1, P Desai 1, A Houzet 1, X Hermant 1, D Cottel 1, A Pritchard 1, T Iwatsubo 1, F Pasquier 1, B Frigard 1, P Conneally 1, M Chartier-Harlin 1, S DeKosky 1, C Lendon 1, D Mann 1, M Kamboh 1, P Amouyel 1
PMCID: PMC1735503  PMID: 12807963

Abstract

Although possession of the ε4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12.

Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism.

Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Aß40, Aß42, Aß total, and Tau loads or the level of microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blacker D., Wilcox M. A., Laird N. M., Rodes L., Horvath S. M., Go R. C., Perry R., Watson B., Jr, Bassett S. S., McInnis M. G. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet. 1998 Aug;19(4):357–360. doi: 10.1038/1243. [DOI] [PubMed] [Google Scholar]
  2. Blacker Deborah, Bertram Lars, Saunders Aleister J., Moscarillo Thomas J., Albert Marilyn S., Wiener Howard, Perry Rodney T., Collins Julianne S., Harrell Lindy E., Go Rodney C. P. Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet. 2003 Jan 1;12(1):23–32. doi: 10.1093/hmg/ddg007. [DOI] [PubMed] [Google Scholar]
  3. Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., Thomas-Anterion C., Michon A., Martin C., Charbonnier F. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664–670. doi: 10.1086/302553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cruts M., van Duijn C. M., Backhovens H., Van den Broeck M., Wehnert A., Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P. H. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43–51. doi: 10.1093/hmg/7.1.43. [DOI] [PubMed] [Google Scholar]
  5. Danik M., Champagne D., Petit-Turcotte C., Beffert U., Poirier J. Brain lipoprotein metabolism and its relation to neurodegenerative disease. Crit Rev Neurobiol. 1999;13(4):357–407. doi: 10.1615/critrevneurobiol.v13.i4.20. [DOI] [PubMed] [Google Scholar]
  6. DeMattos R. B., Brendza R. P., Heuser J. E., Kierson M., Cirrito J. R., Fryer J., Sullivan P. M., Fagan A. M., Han X., Holtzman D. M. Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem Int. 2001 Nov-Dec;39(5-6):415–425. doi: 10.1016/s0197-0186(01)00049-3. [DOI] [PubMed] [Google Scholar]
  7. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fagan A. M., Holtzman D. M. Astrocyte lipoproteins, effects of apoE on neuronal function, and role of apoE in amyloid-beta deposition in vivo. Microsc Res Tech. 2000 Aug 15;50(4):297–304. doi: 10.1002/1097-0029(20000815)50:4<297::AID-JEMT9>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  9. Farrer L. A., Cupples L. A., Haines J. L., Hyman B., Kukull W. A., Mayeux R., Myers R. H., Pericak-Vance M. A., Risch N., van Duijn C. M. 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. 1997 Oct 22;278(16):1349–1356. [PubMed] [Google Scholar]
  10. Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., Runz H., Kuhl S., Bertsch T., von Bergmann K. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 Apr 10;98(10):5856–5861. doi: 10.1073/pnas.081620098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Göritz Christian, Mauch Daniela H., Nägler Karl, Pfrieger Frank W. Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair. J Physiol Paris. 2002 Apr-Jun;96(3-4):257–263. doi: 10.1016/s0928-4257(02)00014-1. [DOI] [PubMed] [Google Scholar]
  12. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997 Apr;20(4):154–159. doi: 10.1016/s0166-2236(96)01030-2. [DOI] [PubMed] [Google Scholar]
  13. Hartmann T. Cholesterol, A beta and Alzheimer's disease. Trends Neurosci. 2001 Nov;24(11 Suppl):S45–S48. doi: 10.1016/s0166-2236(00)01990-1. [DOI] [PubMed] [Google Scholar]
  14. Hayes A., Thaker U., Iwatsubo T., Pickering-Brown S. M., Mann D. M. A. Pathological relationships between microglial cell activity and tau and amyloid beta protein in patients with Alzheimer's disease. Neurosci Lett. 2002 Oct 18;331(3):171–174. doi: 10.1016/s0304-3940(02)00888-1. [DOI] [PubMed] [Google Scholar]
  15. Hixson J. E., Vernier D. T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990 Mar;31(3):545–548. [PubMed] [Google Scholar]
  16. Howland D. S., Trusko S. P., Savage M. J., Reaume A. G., Lang D. M., Hirsch J. D., Maeda N., Siman R., Greenberg B. D., Scott R. W. Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol. J Biol Chem. 1998 Jun 26;273(26):16576–16582. doi: 10.1074/jbc.273.26.16576. [DOI] [PubMed] [Google Scholar]
  17. Iwatsubo T., Odaka A., Suzuki N., Mizusawa H., Nukina N., Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994 Jul;13(1):45–53. doi: 10.1016/0896-6273(94)90458-8. [DOI] [PubMed] [Google Scholar]
  18. Jick H., Zornberg G. L., Jick S. S., Seshadri S., Drachman D. A. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627–1631. doi: 10.1016/s0140-6736(00)03155-x. [DOI] [PubMed] [Google Scholar]
  19. Kang D. E., Saitoh T., Chen X., Xia Y., Masliah E., Hansen L. A., Thomas R. G., Thal L. J., Katzman R. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology. 1997 Jul;49(1):56–61. doi: 10.1212/wnl.49.1.56. [DOI] [PubMed] [Google Scholar]
  20. Kehoe P., Wavrant-De Vrieze F., Crook R., Wu W. S., Holmans P., Fenton I., Spurlock G., Norton N., Williams H., Williams N. A full genome scan for late onset Alzheimer's disease. Hum Mol Genet. 1999 Feb;8(2):237–245. doi: 10.1093/hmg/8.2.237. [DOI] [PubMed] [Google Scholar]
  21. Keller J. N., Hanni K. B., Kindy M. S. Oxidized high-density lipoprotein induces neuron death. Exp Neurol. 2000 Feb;161(2):621–630. doi: 10.1006/exnr.1999.7276. [DOI] [PubMed] [Google Scholar]
  22. Keller J. N., Hanni K. B., Markesbery W. R. Oxidized low-density lipoprotein induces neuronal death: implications for calcium, reactive oxygen species, and caspases. J Neurochem. 1999 Jun;72(6):2601–2609. doi: 10.1046/j.1471-4159.1999.0722601.x. [DOI] [PubMed] [Google Scholar]
  23. Koster M. N., Dermaut B., Cruts M., Houwing-Duistermaat J. J., Roks G., Tol J., Ott A., Hofman A., Munteanu G., Breteler M. M. The alpha2-macroglobulin gene in AD: a population-based study and meta-analysis. Neurology. 2000 Sep 12;55(5):678–684. doi: 10.1212/wnl.55.5.678. [DOI] [PubMed] [Google Scholar]
  24. Ladu M. J., Reardon C., Van Eldik L., Fagan A. M., Bu G., Holtzman D., Getz G. S. Lipoproteins in the central nervous system. Ann N Y Acad Sci. 2000 Apr;903:167–175. doi: 10.1111/j.1749-6632.2000.tb06365.x. [DOI] [PubMed] [Google Scholar]
  25. Lambert J. C., Goumidi L., Vrièze F. W., Frigard B., Harris J. M., Cummings A., Coates J., Pasquier F., Cottel D., Gaillac M. The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease. Hum Mol Genet. 2000 Sep 22;9(15):2275–2280. doi: 10.1093/oxfordjournals.hmg.a018918. [DOI] [PubMed] [Google Scholar]
  26. Luc G., Bard J. M., Arveiler D., Evans A., Cambou J. P., Bingham A., Amouyel P., Schaffer P., Ruidavets J. B., Cambien F. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb. 1994 Sep;14(9):1412–1419. doi: 10.1161/01.atv.14.9.1412. [DOI] [PubMed] [Google Scholar]
  27. Luedecking-Zimmer Erin, DeKosky Steven T., Chen Qi, Barmada M. Michael, Kamboh M. Ilyas. Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum Genet. 2002 Aug 16;111(4-5):443–451. doi: 10.1007/s00439-002-0802-7. [DOI] [PubMed] [Google Scholar]
  28. MacLean C. J., Morton N. E. Estimation of myriad haplotype frequencies. Genet Epidemiol. 1985;2(3):263–272. doi: 10.1002/gepi.1370020304. [DOI] [PubMed] [Google Scholar]
  29. Mayeux R., Lee J. H., Romas S. N., Mayo D., Santana V., Williamson J., Ciappa A., Rondon H. Z., Estevez P., Lantigua R. Chromosome-12 mapping of late-onset Alzheimer disease among Caribbean Hispanics. Am J Hum Genet. 2001 Nov 19;70(1):237–243. doi: 10.1086/324773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Myers Amanda, Wavrant De-Vrieze Fabienne, Holmans Peter, Hamshere Marian, Crook Richard, Compton Danielle, Marshall Helen, Meyer David, Shears Shantia, Booth Jeremy. Full genome screen for Alzheimer disease: stage II analysis. Am J Med Genet. 2002 Mar 8;114(2):235–244. doi: 10.1002/ajmg.10183. [DOI] [PubMed] [Google Scholar]
  31. Pillot T., Goethals M., Najib J., Labeur C., Lins L., Chambaz J., Brasseur R., Vandekerckhove J., Rosseneu M. Beta-amyloid peptide interacts specifically with the carboxy-terminal domain of human apolipoprotein E: relevance to Alzheimer's disease. J Neurochem. 1999 Jan;72(1):230–237. doi: 10.1046/j.1471-4159.1999.0720230.x. [DOI] [PubMed] [Google Scholar]
  32. Rogaeva E., Premkumar S., Song Y., Sorbi S., Brindle N., Paterson A., Duara R., Levesque G., Yu G., Nishimura M. Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA. 1998 Aug 19;280(7):614–618. doi: 10.1001/jama.280.7.614. [DOI] [PubMed] [Google Scholar]
  33. Russo C., Angelini G., Dapino D., Piccini A., Piombo G., Schettini G., Chen S., Teller J. K., Zaccheo D., Gambetti P. Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15598–15602. doi: 10.1073/pnas.95.26.15598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schippling S., Kontush A., Arlt S., Buhmann C., Stürenburg H. J., Mann U., Müller-Thomsen T., Beisiegel U. Increased lipoprotein oxidation in Alzheimer's disease. Free Radic Biol Med. 2000 Feb 1;28(3):351–360. doi: 10.1016/s0891-5849(99)00247-6. [DOI] [PubMed] [Google Scholar]
  35. Scott W. K., Grubber J. M., Conneally P. M., Small G. W., Hulette C. M., Rosenberg C. K., Saunders A. M., Roses A. D., Haines J. L., Pericak-Vance M. A. Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet. 2000 Mar;66(3):922–932. doi: 10.1086/302828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tabner Brian J., Turnbull Stuart, El-Agnaf Omar M. A., Allsop David. Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic Biol Med. 2002 Jun 1;32(11):1076–1083. doi: 10.1016/s0891-5849(02)00801-8. [DOI] [PubMed] [Google Scholar]
  37. Taylor A. E., Yip A., Brayne C., Easton D., Evans J. G., Xuereb J., Cairns N., Esiri M. M., Rubinsztein D. C. Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease. J Med Genet. 2001 Apr;38(4):232–233. doi: 10.1136/jmg.38.4.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wheal H. V., Chen Y., Mitchell J., Schachner M., Maerz W., Wieland H., Van Rossum D., Kirsch J. Molecular mechanisms that underlie structural and functional changes at the postsynaptic membrane during synaptic plasticity. Prog Neurobiol. 1998 Aug;55(6):611–640. doi: 10.1016/s0301-0082(98)00026-4. [DOI] [PubMed] [Google Scholar]
  39. Wu W. S., Holmans P., Wavrant-DeVrièze F., Shears S., Kehoe P., Crook R., Booth J., Williams N., Pérez-Tur J., Roehl K. Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA. 1998 Aug 19;280(7):619–622. doi: 10.1001/jama.280.7.619. [DOI] [PubMed] [Google Scholar]
  40. Yamanaka S., Zhang X. Y., Miura K., Kim S., Iwao H. The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a novel member of the natural killer gene complex with a unique expression profile. Genomics. 1998 Dec 1;54(2):191–199. doi: 10.1006/geno.1998.5561. [DOI] [PubMed] [Google Scholar]
  41. Yao Zhi-Xing, Papadopoulos Vassilios. Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J. 2002 Aug 21;16(12):1677–1679. doi: 10.1096/fj.02-0285fje. [DOI] [PubMed] [Google Scholar]

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