Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome
Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome
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DOI：
10.1016/j.neulet.2007.08.042
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发表时间：
2007-09-25
影响因子：
2.5
通讯作者：
Schupf, Nicole
中科院分区：
文献类型：
--
作者：
Lee, Joseph. H.;Chulikavit, Maruit;Schupf, Nicole
最近的报告表明，分拣蛋白相关受体基因（SORL 1）的变异增加了北方欧洲人、西班牙裔、非洲裔美国人和以色列阿拉伯人群体中迟发性阿尔茨海默病（AD）的风险。SORL 1指导淀粉样前体蛋白（APP）的运输，SORL 1的低表达可能导致P淀粉样肽的过度表达。成人唐氏综合征（DS）过度表达APP，并具有早发性和AD的高风险。我们调查了SORL 1基因的7种变异与208名基线年龄为45-70岁的DS成人的发病年龄和AD风险的关系。通过纽约州发育残疾服务系统确定参与者，并每隔18个月进行随访。来自认知评估、照顾者访谈、医疗记录审查和神经系统检查的信息被用来确定痴呆的诊断。rs 556349中次要T等位基因和rs 536360中次要C等位基因的纯合性与较晚的发病年龄和AD风险降低相关（HR = 0.26，95%CI：0.08-0.86; HR = 0.40，95%CI：0.16-0.98）。与至少有一个主要等位基因的个体相比，这些等位基因纯合子个体的平均发病年龄大约晚4年。这些发现表明SORL 1的变异与AD有一定的关联。此外，与早期研究相比，我们没有观察到与AD相关的相同等位基因，这表明这些SNP与推定的功能变体处于连锁不平衡（LD），或者SORL 1基因的表达及其与APP的相互作用可能被唐氏综合征特征的极高水平的APP修饰。因此，需要进一步的研究，以确定功能变异，影响AD的风险，在这个独特的弱势群体。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African-American and Isreali-Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of P amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45-70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08-0.86; and HR = 0.40, 95% CI: 0.16-0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population. (c) 2007 Elsevier Ireland Ltd. All rights reserved.