ssociation and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease
ssociation and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease
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DOI：
10.1001/archneurol.2011.155
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发表时间：
2011-08-01
影响因子：
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通讯作者：
Goate, Alison M.
中科院分区：
文献类型：
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作者：
Cruchaga, Carlos;Nowotny, Petra;Goate, Alison M.
背景：载脂蛋白E（APOE）是晚发性阿尔茨海默病（LOAD）最具统计学意义的遗传危险因素。APOE基因周围的连锁不平衡模式使得很难确定是否所有的关联信号都来自APOE或是否存在来自附近基因的独立信号。目的：试图复制最近报道的APOE 3-TOMM 40单倍型与发病风险和年龄的关联。设计：我们使用标准技术对一个大型病例对照系列、一个有脑脊液生物标志物数据的系列和脑组织中APOE-TOMM 40区域的几种多态性进行基因分型。Alzheimer's Disease Research Center.Participants：Research volunteers who were cognitive normal or had Alzheimer disease.Main Outcome Measures：Disease status and age at onset.Results：我们没有复制先前报道的polyT多态性（rs 10524523）与发病风险和年龄的相关性。我们发现rs 10524523与APOE 33纯合子的LOAD风险之间存在显著相关性，但与先前报道的相关性方向相反（在本研究中，病例与对照组中非常长的等位基因代表性不足（P=.004））。我们发现rs 10524523与脑脊液tau蛋白或β-淀粉样蛋白42水平或TOMM 40或APOE基因表达之间没有关联。尽管我们没有复制APOE 3-TOMM 40单倍型与发病年龄之间的早期关联，我们观察到，在一个大的病例中，多聚T多态性与APOE 33纯合子LOAD的风险相关-控制系列，但在相反的方向，在以前的研究。
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 beta-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.