Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.
Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.
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DOI：
10.1038/mp.2011.24
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发表时间：
2012-02
影响因子：
11
通讯作者：
Van Broeckhoven, C.
中科院分区：
文献类型：
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作者：
Brouwers, N.;Van Cauwenberghe, C.;Engelborghs, S.;Lambert, J-C;Bettens, K.;Le Bastard, N.;Pasquier, F.;Montoya, A. Gil;Peeters, K.;Mattheijssens, M.;Vandenberghe, R.;De Deyn, P. P.;Cruts, M.;Amouyel, P.;Sleegers, K.;Van Broeckhoven, C.
两项多中心全基因组关联（GWA）研究提供了大量证据，表明补体受体1基因（CR 1）与阿尔茨海默病（AD）的遗传病因有关。CR 1编码一个大的跨膜受体，在免疫补体级联反应中起关键作用。我们在佛兰德斯-比利时队列（n=1883）中对GWA CR 1相关性进行了遗传随访，并研究了位于CR 1位点的单核苷酸多态性（SNP）对AD风险和脑脊液（CSF）生物标志物水平的影响。我们获得了一个CR 1风险单倍型的显著相关性（Padj<0.03;比值比（OR）=1.24（95%置信区间（CI）：1.02-1.51）），并且单倍型关联在携带载脂蛋白E（APOE）β 4等位基因的个体中最强（Padj<0.006; OR=1.50（95%CI：1.08-2.09））。此外，4个SNP与CSF淀粉样蛋白Aβ1−42水平升高相关，表明CR 1蛋白在Aβ代谢中的作用。此外，我们量化了CR 1中与低拷贝重复序列（LCR）相关的拷贝数变异（CNV），产生了不同的CR 1亚型CR 1-F和CR 1-S，并在CR 1-S携带者中获得了显著的相关性。我们在法国队列（n=2003）中重复了CR 1 CNV相关性发现，并在联合队列中计算出OR为1.32; 95%CI：1.10-1.59（P=0.0025）。我们的数据表明，常见的AD风险相关性可以很好地解释为CR 1-S的存在增加了C3 b/C4 b和辅因子活性位点的数量，CR 1-S携带者中AD风险为30%。CR 1-S在免疫补体级联中的不同功能作用如何精确地促成AD发病机制将需要额外的功能研究。
Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders–Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (Padj<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02–1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (Padj<0.006; OR=1.50 (95% CI: 1.08–2.09)). Also, four SNPs correlated with increased CSF amyloid Aβ1−42 levels, suggesting a role for the CR1 protein in Aβ metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10–1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
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通讯作者：
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影响因子：
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3
作者：
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通讯作者：
Armengol L
DOI：
10.1084/jem.168.5.1699
发表时间：
1988-11-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Fearon DT