SUSCEPTIBILITY ALLELES IN IDE REGION ON CHROMOSOME 10

努力识别具有影响晚发性AD(LOAD)易感性的等位基因 在逻辑上从连锁到关联，然后到特定易感性的鉴定 等位基因。使用血浆淀粉样β蛋白(Abeta42)水平作为负载的中间定量表型，我们在10号染色体(Ch10)上获得了大约80厘米器官(Cm)的连锁。在对受影响的负载同胞对的研究中，独立地获得了与相同区域的连锁。为了追求这些发现，我们现在已经确定了三个CH10基因(VR22、PLAU和IDE)，它们具有与LOAD和/或血浆Abeta42密切相关的变异。拟议的研究完全集中在集成开发环境上。来自IDE基因敲除小鼠的令人信服的生物学证据表明，胰岛素降解酶通常参与Abeta的降解，因此IDE显然是一个很好的候选基因。在我们的MCJ系列中，在来自苏格兰和瑞典的多个病例对照系列中，LOAD与Brookes组显示的与AD显著(p&lt；0.01)或极显著(p&lt；10[-9])相同的IDE单倍型显著相关(p&lt；10[-7])。在我们的扩展负荷系列中，这些相同的单倍型与血浆Abeta42显著相关。本研究的目的是确定IDE区域的负荷易感性等位基因。在所有来自MCJ系列的LOAD患者中，我们将彻底筛选IDE基因的编码和可能的调节区，如果必要的话，还将筛查相邻基因。我们发现的SNP(从我们的IDE初始筛查中预计大约有60个)将使用两阶段统计方法进行分析，以确定与LOAD和血浆Abeta42表现出最强、最具重复性的关联的假定易感等位基因集。然后将评估与负荷相关的生物效应的强关联SNPs。为了便于分析推测的调控区域中的变异，并扩大我们的病例对照队列的规模，我们将从神经病理学核心提供的大量冷冻负荷脑中提取cDNA和基因组DNA。

The effort to identify genes with alleles that influence susceptibility to late onset AD (LOAD) proceeds logically from linkage to association and then to identification of specific susceptibility alleles. Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for LOAD, we obtained linkage at approximately 80 centimorgans (cM) on chromosome 10 (Ch10). Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Pursuing these findings, we have now identified three Ch10 genes (VR22, PLAU, and IDE) with variants that show strong association with LOAD and/or plasma Abeta42. The proposed study focuses exclusively on IDE. There is compelling biological evidence from IDE knockout mice that the insulin degrading enzyme is normally involved in Abeta degradation, so IDE is clearly an excellent candidate gene. In our MCJ series, LOAD showed highly significant (p<10[-7]) association with the same IDE haplotypes that the Brookes group showed to be significantly (p<0.01) or highly significantly (p<10[-9]) associated with AD in multiple case-control series from Scotland and Sweden. These same haplotypes showed significant association with plasma Abeta42 in our extended LOAD series. The goal of this study is to identify the LOAD susceptibility alleles in the IDE region. In all LOAD patients from the MCJ series, we will thoroughly screen the coding and putative regulatory regions of the IDE gene and, if necessary, adjacent genes. The SNPs that we find (approximately 60 are expected from our initial screen of IDE) will be analyzed using a two stage statistical approach to identify the set of putative susceptibility alleles that show strongest, most reproducible association with LOAD and with plasma Abeta42. Strongly associating SNPs will then be evaluated for biological effects relevant to LOAD. To facilitate analysis of variants in putative regulatory regions and to increase the size of our case-control cohort, we will prepare cDNA and genomic DNA from the large number of frozen LOAD brains available through the Neuropathology Core.