Susceptibility Alleles in IDE Region on Chromosome 10

10 号染色体 IDE 区域的易感性等位基因

• 批准号: 7618218
• 负责人: STEVEN G YOUNKIN
• 金额: $ 20.52万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7618218
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Biological; Brain; Candidate Disease Gene; Chromosomes, Human, Pair 10; Code; Collaborations; Complementary DNA; DNA; Freezing; Gene Expression; Genes; Genetic Variation; Genomics; Goals; Haplotypes; Insulinase; Knockout Mice; Linkage Disequilibrium; Nucleic Acid Regulatory Sequences; Numbers; PLAU gene; Patients; Phenotype; Plasma; Predisposition; Proteins; RNA Splicing; Research; Research Infrastructure; Research Proposals; Resources; Risk; Scotland; Series; Staging; Sweden; Urokinase; Variant; Work; case control; cohort; neuropathology; size

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.

努力识别具有影响迟到AD敏感性（负载）敏感性的等位基因的基因 从链接到关联，然后识别特定易感性的逻辑收益 等位基因。使用血浆淀粉样β蛋白（ABETA42）水平作为载荷定量表型的中间体，我们在染色体10（CH10）的大约80厘米（CM）上获得了连锁。在对受影响的负载SIB对的研究中独立获得与同一区域的联系。追求这些发现，我们现在已经确定了三个CH10基因（VR22，PLAU和IDE），它们具有与负载和/或等离子体Abeta42相关的变体。拟议的研究仅专注于IDE。从IDE基因敲除小鼠中有令人信服的生物学证据表明，胰岛素降解酶通常参与ABETA降解，因此IDE显然是一个极好的候选基因。在我们的MCJ系列中，载荷与Brookes组显示出显着（P <0.01）或高度显着（P <10 [-9]）相同的IDE单倍型（P <10 [-7]）的关联非常显着（P <10 [-9]）。这些相同的单倍型在我们的扩展负载序列中与等离子体Abeta42显示了显着关联。这项研究的目的是确定IDE区域中的负载敏感性等位基因。在MCJ系列中的所有负载患者中，我们将彻底筛选IDE基因的编码和推定调节区域，并在必要时进行相邻基因。我们发现的SNP（从我们的初始IDE屏幕上预计大约60个）将使用两级统计方法分析，以识别一组推定的易感性等位基因，这些敏感性等位基因表现出最强，最可重复的与负载和等离子体Abeta42的关联。然后，将评估与负载相关的生物学效应的强烈关联。为了促进对推定调节区域中变体的分析并增加了病例对照组的大小，我们将从通过神经病理学核心可用的大量冷冻负载大脑中制备cDNA和基因组DNA。