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首页> 外文期刊>Neuron >GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
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GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

机译：GAB2等位基因改变了APOE epsilon4携带者中阿尔茨海默氏症的风险。

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摘要

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.
机译：载脂蛋白E（APOE）epsilon4等位基因是晚期阿尔茨海默氏病（LOAD）的最佳遗传风险因素。我们对502,627个单核苷酸多态性（SNP）进行了全基因组调查，以表征和确认其他LOAD敏感性基因。在神经病理学证实的发现，神经病理学证实的复制以及临床特征性复制队列的1411例病例和对照的epsilon4载体中，LOAD与来自GRB相关结合蛋白2（GAB2）基因的6个SNP和涉及整个GAB2基因的常见单倍型相关。 SNP rs2373115（p = 9 x 10（-11））的比值比为4.06（置信区间2.81-14.69），与APOE epsilon4相互作用以进一步改变风险。 GAB2在病理脆弱的神经元中过表达;在神经元，缠结神经元和营养不良性神经炎中检测到Gab2蛋白。和干扰GAB2基因表达会增加tau磷酸化。我们的发现表明，GAB2可改变APOE epsilon4携带者的LOAD风险，并影响阿尔茨海默氏症的神经病理学。

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