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

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...

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Published inJournal of medical genetics Vol. 40; no. 6; pp. 424 - 430
Main Authors Lambert, J-C, Luedecking-Zimmer, E, Merrot, S, Hayes, A, Thaker, U, Desai, P, Houzet, A, Hermant, X, Cottel, D, Pritchard, A, Iwatsubo, T, Pasquier, F, Frigard, B, Conneally, P M, Chartier-Harlin, M-C, DeKosky, S T, Lendon, C, Mann, D, Kamboh, M I, Amouyel, P
Format Journal Article
LanguageEnglish
Published London BMJ Publishing Group Ltd 01.06.2003
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Summary: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, Aβ40, Aβ42, Aβ 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.
Bibliography:Correspondence to:
 Dr J-C Lambert, Unité INSERM 508, Institut Pasteur de Lille, BP 245, 1 rue du Professeur Calmette, 59019 Lille Cédex, France;
 jean-charles.lambert@pasteur-lille.fr
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ISSN:0022-2593
1468-6244
1468-6244
DOI:10.1136/jmg.40.6.424