Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism
Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism
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DOI：
10.1016/j.neurobiolaging.2012.07.001
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发表时间：
2012-12-01
影响因子：
4.2
通讯作者：
Rogaeva, Ekaterina
中科院分区：
文献类型：
--
作者：
Hazrati, Lili-Naz;Van Cauwenberghe, Caroline;Rogaeva, Ekaterina
CR 1基因是全基因组关联研究（genome-wide association studies，GWAS）发现的一个新的阿尔茨海默病（Alzheimer's disease，AD）基因。最近，我们发现AD的风险可以解释为18-腺苷酸酶插入负责补体成分（3b/4 b）受体1（CR 1）-S亚型。我们研究了加拿大数据集中CR 1亚型与AD的相关性。此外，我们对标记GWAS显著CR 1单核苷酸多态性的rs 4844610进行基因分型。与F/F基因型相比，具有F/S基因型的个体患AD的风险增加1.8倍（p调整= 0.003），而rs 4844610仅略微显著（p调整= 0.024）。脑样品的分析表明，CR 1-S同种型以低于CR 1-F的蛋白质水平表达（p < 0.0001），因此可能与补体活化增加相关。有趣的是，我们的神经病理学结果表明，CR 1在神经元中的表达模式在F/F和F/S基因型之间是不同的（丝状与囊泡样轮廓）。此外，双标记研究支持CR 1在神经元中的差异分布（内质网中室与溶酶体）。这些观察结果表明，CR 1-S和CR 1-F亚型可以在神经元中以不同的方式加工。总之，我们的研究结果支持CR 1-S亚型解释GWAS信号，并为CR 1相关疾病机制的研究开辟了新的前景。(C)2012 Elsevier Inc. All rights reserved.
CR1 is a novel Alzheimer's disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS-significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms. (C) 2012 Elsevier Inc. All rights reserved.