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Original Contributions |

Association and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease

Carlos Cruchaga, PhD; Petra Nowotny, PhD; John S. K. Kauwe, PhD; Perry G. Ridge, MS; Kevin Mayo, BA; Sarah Bertelsen, MS; Anthony Hinrichs, PhD; Anne M. Fagan, PhD; David M. Holtzman, MD; John C. Morris, MD; Alison M. Goate, PhD; for the Alzheimer's Disease Neuroimaging Initiative
Arch Neurol. 2011;68(8):1013-1019. doi:10.1001/archneurol.2011.155.
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Background Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene.

Objective To attempt to replicate a recently reported association of APOE 3–TOMM40 haplotypes with risk and age at onset.

Design We used standard techniques to genotype several polymorphisms in the APOE–TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue.

Setting Alzheimer's Disease Research Center.

Participants Research volunteers who were cognitively normal or had Alzheimer disease.

Main Outcome Measures Disease status and age at onset.

Results We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression.

Conclusions Although we did not replicate the earlier association between the APOE 3–TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

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Figure. rs10524523 is not associated with age at onset of late-onset Alzheimer disease (LOAD) in apolipoprotein E (APOE) 33 carriers. A, Age at onset was analyzed for association with rs10524523 in 282 APOE 33 LOAD cases from the Alzheimer Disease Research Center at Washington University (WU-ADRC) series using the Kaplan-Meier method and was tested for significant differences using the log-rank test. B, Age at onset was analyzed for association with rs10524523 in 282 LOAD cases and 213 controls from the WU-ADRC series with an APOE 33 genotype by the Kaplan-Meier method and was tested for significant differences using the log-rank test. In both analyses, the short-short (S-S), short–very long (S-VL), and very long–very long (VL-VL) genotypes are highlighted because they were the most frequent in these strata. No significant differences in the survival curves were found (P > .05). L-L indicates long-long; L-VL, long–very long; and S-L, short-long.

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