Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Neurobiol Aging. 2011 Nov;32(11):2107.e7-17. doi: 10.1016/j.neurobiolaging.2011.05.023. Epub 2011 Jul 14.
We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3' to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.
我们报告了 APOE 簇基因（APOE、APOC1、APOC4、APOC2 和 TOMM40）启动子和调控区在阿尔茨海默病（AD）风险以及从轻度认知障碍（MCI）进展为 AD 中的精细定位/测序结果。在 29 名进展为痴呆的 MCI 受试者的长距离测序中发现了 7 个新变体。在一个包含大量 AD、MCI 和对照受试者的样本（n=1453）中对两个潜在相关的新变体和 34 个单核苷酸多态性（SNP）进行了基因分型。在我们的样本中，在没有 APOE ε4 的情况下，几乎没有观察到全局关联信号。尽管未经多测试校正（未校正的 p 值分别为 0.0099 和 0.01），但 rs5158（APOC4 内含子 1）和 rs10413089（APOC2 3'）显示出独立于 APOE ε4 相关风险的 AD 风险增加趋势。有趣的是，rs10413089 在独立系列中也表现出类似的效果。发现样本的分析显示，TOMM40 单核苷酸多态性与从 MCI 阶段进展到 AD（rs59007384 和 rs11556510）以及从 MCI 状态进展到 AD 的时间更短（rs10119）相关，尽管这些结果在独立系列中无法复制。需要进一步的研究来探讨 APOE 簇变体在 AD 风险中的作用。
