Is α-T catenin (VR22) an Alzheimer's disease risk gene?
Is α-T catenin (VR22) an Alzheimer's disease risk gene?
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DOI：
10.1136/jmg.2005.039263
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Tanzi, Rudolph E.
中科院分区：
文献类型：
--
作者：
Bertram, Lars;Mullin, Kristina;Tanzi, Rudolph E.
背景：最近，关于α - t连环蛋白基因（VR22; CTNNA3）遗传变异在阿尔茨海默病风险中的潜在作用，发表了相互矛盾的报道。在这些论文中，关联的证据主要在阿尔茨海默病的多重家族中观察到，而散发性阿尔茨海默病的病例对照样本主要是阴性的。方法：在对与10q21染色体相关的阿尔茨海默病多家族VR22进行测序后，我们发现了一种新的非同义（Ser596Asn; rs4548513）单核苷酸多态性（SNP）。在两个独立的阿尔茨海默病家族样本中评估了这个和四个非编码snp，其中一个来自437个阿尔茨海默病多重家族的1439名受试者，另一个来自217个不一致兄弟姐妹的489名受试者。结果：在多重样本中，观察到与Ser596Asn SNP的弱关联，主要是在迟发性阿尔茨海默病的家庭中（p = 0.02）。然而，这种关联似乎并没有对我们和其他人之前报道的10号染色体阿尔茨海默病联系信号做出实质性贡献。没有证据表明该基因与阿尔茨海默病多重家族中另外四个snp中的任何一个有关联。最后，Ser596Asn的变化与独立不一致的兄弟姐妹样本中患阿尔茨海默病的风险无关。结论：这是第一个报告VR22中潜在功能的非同义SNP与阿尔茨海默病风险之间关联证据的研究。由于潜在的影响可能很小，而且只在有多名患病成员的家庭中出现，因此这一发现对整个人群的意义仍有待确定。
Background: Recently, conflicting reports have been published on the potential role of genetic variants in the alpha-T catenin gene (VR22; CTNNA3) on the risk for Alzheimer's disease. In these papers, evidence for association is mostly observed in multiplex families with Alzheimer's disease, whereas case-control samples of sporadic Alzheimer's disease are predominantly negative.Methods: After sequencing VR22 in multiplex families with Alzheimer's disease linked to chromosome 10q21, we identified a novel non-synonymous (Ser596Asn; rs4548513) single nucleotide polymorphism (SNP). This and four non-coding SNPs were assessed in two independent samples of families with Alzheimer's disease, one with 1439 subjects from 437 multiplex families with Alzheimer's disease and the other with 489 subjects from 217 discordant sibships.Results: A weak association with the Ser596Asn SNP in the multiplex sample, predominantly in families with late-onset Alzheimer's disease (p = 0.02), was observed. However, this association does not seem to contribute substantially to the chromosome 10 Alzheimer's disease linkage signal that we and others have reported previously. No evidence was found of association with any of the four additional SNPs tested in the multiplex families with Alzheimer's disease. Finally, the Ser596Asn change was not associated with the risk for Alzheimer's disease in the independent discordant sibship sample.Conclusions: This is the first study to report evidence of an association between a potentially functional, non-synonymous SNP in VR22 and the risk for Alzheimer's disease. As the underlying effects are probably small, and are only seen in families with multiple affected members, the population-wide significance of this finding remains to be determined.