Abstract
The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5′ untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE ε4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.
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Martinez M, Campion D, Brice A, et al. Apolipoprotein E ε4 allele and familial aggregation of Alzheimer disease Arch Neurol 1998 55: 810–816
Pericak-Vance MA, Bass MP, Yamaoka LH, et al. Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12 JAMA 1997 278: 1237–1241
Zubenko GS, Hughes HB, Sgifler JS, Hurtt MR, Kaplan BB . A genome survey for novel Alzheimer disease risk loci : results at 10-cM resolution Genomics 1998 50: 121–128
Rogaeva E, Premkumar S, Song Y, et al. Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity JAMA 1998 280: 614–618
Kehoe P, Wavrant-de Vriéze F., Crook R, et al. A full genome scan for late onset Alzheimer's disease Hum Mol Genet 1999 8: 237–245
Scott WK, Grubber JM, Abou-Donia SM, et al. Further evidence linking late-onset Alzheimer disease with chromosome 12 JAMA 1999 281: 513–514. Letter
Fagan AM, Bu G, Sun Y, Daugherty A, Holtzman DM . Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein J Biol Chem 1996 271: 30121–30125
Holtzman DM, Pitas RE, Kilbridge J, et al. Low density lipoprotein receptor related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line Proc Natl Acad Sci USA 1995 92: 9480–9484
Kounnas MZ, Moir RD, Rebeck GW, et al. LDL receptor-related protein, a multifunctional apoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation Cell 1995 82: 331–340
Rebeck GW, Harr SD, Strickland DK, Hyman BT . Multiple, diverse senile plaque associated proteins are ligands of an apolipoprotein receptor, the alpha 2 macroglobulin/low density lipoprotein-related protein Ann Neurol 1995 37: 211–217
Harris M, Sanghera DK, Kamboh MI . Two new alleles in the tetranucleotide repeat polymorphism in the LDL-receptor-related protein (LRP) gene Clin Genet 1996 50: 54–55
Lendon CL, Talbot CJ, Craddock NJ, et al. Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a caucasian population Neurosci lett 1997 222: 187–190
Lambert J-C, Chartier-Harlin M-C, Cottel D, et al. Is the LDL receptor-related protein involved in Alzheimer's disease? Neurogenetics 1999 2: 109–113
Fallin D, Kundtz A, Town T, et al. No association between the low density lipoprotein receptor-related protein (LRP) gene and late-onset Alzheimer's disease in a community-based sample Neurosci Lett 1997 233: 145–147
Clatworthy AE, Gomez-Isla T, Rebeck GW, Wallace RB, Hyman BT . Lack of association of a polymorphism in the low-density lipoprotein receptor-related protein gene with Alzheimer disease Arch Neurol 1997 54: 1289–1292
Kamboh MI, Ferrell RE, DeKosky ST . Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor-related protein gene Neurosci Lett 1998 244: 65–68
Scott WK, Yamaoka LH, Bass MP, et al. No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease Neurogenetics 1998 1: 179–183
Kang DE, Saitoh T, Chen X, et al. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease Neurology 1997 49: 56–61
Hollenbach E, Ackermann S, Hyman BT, Rebeck GW . Confirmation of an association between a polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene and Alzheimer's disease Neurology 1998 50: 1905–1907
Baum L, Chen L, Ng H-K, et al. Low density lipoprotein receptor related protein gene exon 3 polymorphism association with Alzheimer's disease in Chinese Neurosci Lett 1998 247: 33–36
Lambert J-C, Wavrant-de Vriéze F, Amouyel P, Chartier-Harlin M-C . Association at LRP gene locus with sporadic late-onset Alzheimer's disease Lancet 1998 351: 1787–1888
Woodward R, Singleton AB, Gibson AM, Edwardson JA, Morris CM . LRP gene and late-onset Alzheimer's disease Lancet 1998 352: 239–240
Beffert U, Arguin C, Poirier J . The polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene is weakly associated with Alzheimer's disease Neurosci Lett 1999 259: 29–32
Thomson G . The effect of a selected locus on linked neutral loci Genetics 1977 85: 753–788
Robinson WP, Cambon-Thomsem A, Borot N, Klitz W, Thomson G . Selection, hitchhiking and disequilibrium analysis at three linked loci with application to HLA data Genetics 1991 129: 931–948
Thomson G, Baur MP . Third order linkage disequilibrium Tissue Antigens 1984 24: 250–255
McKahn G, Drachman D, Folstein M, Karzman R, Price D, Stadlan E . Clinical diagnosis of Alzheimer's disease : report of the NINCDS-ADRA work group Neurology 1984 34: 939–944
Zuliani G, Hobbs HH . Tetranucleotide length polymorphism 5′ of the alpha 2-macroglobulin receptor (A2MR)/LDL receptor-related protein (LRP) gene Hum Mol Genet 1994 3: 215
Xie X, Ott J . Testing linkage disequilibrium between a disease gene and marker loci Am J Hum Genet 1993 53: 1107
Terwilliger J, Ott J . Handbook of Human Genetic Linkage Johns Hopkins University Press, Baltimore 1994
Fallin D, Schorck NJ . Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data Am J Hum Genet 2000 67: 947–959
Acknowledgements
We thank all members of the French Alzheimer's disease genetic study group for their contributions; Jacqueline Bou, Christiane Penet and Yolaine Pothin for their technical assistance. We are most grateful to all participants in the study.
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Verpillat, P., Bouley, S., Campion, D. et al. Use of haplotype information to test involvement of the LRP gene in Alzheimer's disease in the French population. Eur J Hum Genet 9, 464–468 (2001). https://doi.org/10.1038/sj.ejhg.5200644
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DOI: https://doi.org/10.1038/sj.ejhg.5200644
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