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O1‐01‐06: Risk For Alzheimer's Associated with a Copy Number Variation In The Complement Receptor 1 Increasing C3b/C4b Binding Sites
Author(s) -
Brouwers Nathalie,
Van Cauwenberghe Caroline,
Engelborghs Sebastiaan,
Lambert JeanCharles,
Bettens Karolien,
Le Bastard Nathalie,
Pasquier Florence,
Vandenberghe Rik,
De Deyn Peter,
Cruts Marc,
Amouyel Philippe,
Sleegers Kristel,
Van Broeckhoven Christine
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2436
Subject(s) - single nucleotide polymorphism , copy number variation , complement receptor 1 , locus (genetics) , allele , biology , haplotype , genome wide association study , genetic association , cohort , medicine , genetics , apolipoprotein e , oncology , genotype , disease , gene , complement system , immune system , genome
TOMM40. In this study we tried to replicate a recently reported association of a PolyT polymorphism in TOMM40 with age at onset among APOE 33 homozygotes. Methods: Risk for disease and age at onset analyses were performed in a total of 1594 LOAD cases (474 APOE 33) and 1190 cognitively normal controls (701 APOE 33). Rs7412 and rs429358, which define the APOE e2/e3/e4 isoforms, rs1160985, and rs4420638 (TOMM40) were genotyped using Kaspar or TaqMan genotyping technology. The polyT repeat inintron 6 of TOMM40 (rs10524523) was genotyped using fluorescence-based fragment size analysis. Expression studies were carried out using cDNA obtained from the parietal lobes of 82 AD cases and 39 cognitively normal individuals (CDR 1⁄4 0). Association with CSF tau, tau phosphorylated at threonine 181 (ptau181), Ab42, and Ab40 and APOE levels was tested in an independent series of 474 samples from the WU-ADRC and 259 samples from the Alzheimer’s Disease Neuroimaging Initiative. Results: We failed to find an association between any genotyped SNP and age at onset after including APOE isoform genotype in the model. We did find a significant association between the PolyT polymorphism (rs10524523) and risk for LOAD among APOE 33 homozygotes. In the APOE 33 substratum the frequency of thers 10524523 very-long allele was decreased in cases compared to controls (p 1⁄4 0.004; OR 1⁄4 0.78; 95%CI 1⁄4 0.65-0.95), which is the opposite direction to that reportedin the initial study. We found no association between rs10524523 and CSF tau orAb42levels or TOMM40 or APOE gene expression. Conclusions: Although we were unable to replicate the earlier association between the PolyT polymorphism and age at onset, we did observe that the PolyT polymorphism is associated with risk for LOAD among APOE 33 homozygotes in a large case-control series. The very-long allele of the polyT variant, which had previously been reported to be associated with earlier age at onset, was associated with a lower risk for AD. The polyT variant or the SNP, rs1160985, which is in high LD (r1⁄40.93) among the APOE 33 carriers, could be used to identify subgroups of APOE 33 individuals with different risk for LOAD.