Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Mol Psychiatry. 2012 Feb;17(2):223-33. doi: 10.1038/mp.2011.24. Epub 2011 Mar 15.
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 (P(adj)<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 (P(adj)<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.
两项多中心全基因组关联（GWA）研究提供了充分的证据，表明补体受体 1 基因（CR1）参与了阿尔茨海默病（AD）的遗传病因。CR1 编码一种大型跨膜受体，在免疫补体级联反应中起着至关重要的作用。我们在佛兰德-比利时队列（n=1883）中对 GWA CR1 关联进行了遗传随访，并研究了位于 CR1 基因座的单核苷酸多态性（SNP）对 AD 风险和脑脊液（CSF）生物标志物水平的影响。我们发现了一个 CR1 风险单倍型的显著关联（P(adj)<0.03；比值比（OR）=1.24（95%置信区间（CI）：1.02-1.51）），并且在携带载脂蛋白 E（APOE）ɛ4 等位基因的个体中，单倍型关联最强（P(adj)<0.006；OR=1.50（95% CI：1.08-2.09））。此外，有四个 SNP 与 CSF 淀粉样蛋白 Aβ₁₋₄₂水平升高相关，提示 CR1 蛋白在 Aβ 代谢中起作用。此外，我们对 CR1 中的低拷贝重复（LCR）相关拷贝数变异（CNV）进行了定量分析，产生了不同的 CR1 同工型 CR1-F 和 CR1-S，并在 CR1-S 携带者中获得了显著的关联。我们在法国队列（n=2003）中复制了 CR1 CNV 关联发现，并在合并队列中计算出，OR 为 1.32；95%CI：1.10-1.59（P=0.0025）。我们的数据表明，常见的 AD 风险关联很可能可以通过 CR1-S 的存在来解释，CR1-S 增加了 C3b/C4b 和辅助因子活性位点的数量，并使 CR1-S 携带者的 AD 风险增加 30%。CR1-S 在免疫补体级联反应中的不同功能作用如何精确地导致 AD 发病机制，还需要进一步的功能研究。
