Plasma AB as a Surrogate Genetic Marker for LOAD

血浆 AB 作为 LOAD 的替代遗传标记

• 批准号: 7877959
• 负责人: STEVEN G YOUNKIN
• 金额: $ 31.01万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877959
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Brain; Chromosomes; Chromosomes, Human, Pair 10; Collaborations; Complementary DNA; Disease; Elderly; Enzyme Gene; Enzymes; Family; Follow-Up Studies; Functional RNA; Gene Expression; Gene Targeting; Genes; Genetic Markers; Genotype; Individual; Insulin; Insulinase; Island; Late Onset Alzheimer Disease; Link; Linkage Disequilibrium; Location; Maps; Messenger RNA; Methods; Other Genetics; PLAU gene; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Plasma; Populations at Risk; Predisposition; Prevention; Process; Proteins; Quantitative Trait Loci; RNA Splicing; Reporting; Research Infrastructure; Risk; Sampling; Series; Short Tandem Repeat; Societies; Urokinase; Variant; Work; apolipoprotein E-4; base; beta-site APP cleaving enzyme 1; case control; disorder risk; genetic association; genetic linkage analysis; genome wide association study; genome-wide; improved; novel; novel therapeutics; presenilin-1; presenilin-2; prevent; risk benefit ratio

DESCRIPTION (provided by applicant): In an effort to understand and to overcome the factors that thwart replication of genetic association studies, we recently studied variants in the conserved regions of the gene (IDE) that encodes the insulin/AB degrading enzyme gene in considerable detail. A remarkably high percentage of these variants had modest effects that showed replicable association when analyzed in our large case/control series. Based on these results, our current working hypothesis is that progress in identifying novel LOAD genes has been slow because most LOAD genes are like IDE; they have multiple susceptibility alleles with modest effect size. The effect of genes with powerful variants like the ApoE 4 allele is easily detected and replicated in small case/control series. But the net effect of genes with multiple susceptibility alleles that have modest effects, though substantial, cannot be detected and replicated well unless large case/control series are employed to evaluate a set of variants selected for their likely functional effect. Using the scientific infrastructure developed in the last cycle we propose to pursue this hypothesis by targeting genes in the AB processing pathway. We will perform an unbiased, genome-wide search for AB QTLs likely to harbor novel LOAD genes in the AB processing pathway. In addition, we will search thoroughly for and examine the function of additional susceptibility alleles in the known, major genes of the AB processing pathway. Our specific aims are to (1) perform whole genome scans to identify novel quantitative trait loci (QTLs) linked to plasma AB levels, (2) identify novel LOAD susceptibility alleles by using multiple, large case control series to analyze the variants in conserved regions of major genes in the AB processing pathway (SORL1, APP, IDE, MME, ECE1, PLAU, BACE1, PSEN1, PSEN2, and VR22), and (3) evaluate the functional effects of the susceptibility alleles identified in specific aim 2. Depending on the specific location of each susceptibility allele identified, function will be analyzed by evaluating the effect of the variant on (i) plasma AB and/or (ii) brain mRNA. Our recent results suggest that many susceptibility alleles may act by altering gene expression or splicing. There is strong evidence that reducing the AB42 peptide in normal elderly subjects could prevent Alzheimer's disease (AD), a disorder that inflicts enormous suffering and financial loss on our society. To perform affordable prevention trials and administer drugs to normal elderly people with an acceptable risk/benefit ratio, methods must be developed for identifying those elderly individuals who are at increased risk for AD. In this application, we propose experimentation to identify many genes with variants that alter AB42 thereby influencing risk for AD; we do so because each new AD gene identified opens new therapeutic possibilities and improves our ability to identify the at risk population.

描述（由申请人提供）：为了理解和克服挫败遗传关联研究的复制的因素，我们最近研究了基因（IDE）保守区域中编码胰岛素/AB降解酶基因的变体。这些变体中有很高的比例具有适度的效果，在我们的大病例/对照组中进行分析时，这些效应显示出可复制的关联。基于这些结果，我们当前的工作假设是，鉴定新负荷基因的进展一直很慢，因为大多数负载基因都像IDE一样。它们具有多个具有适度效果大小的敏感性等位基因。在小病例/控制系列中很容易检测并复制具有强大变体（如APOE 4等位基因）的效果。但是，除非采用大型病例/控制序列来评估一组用于其可能功能效应的变体，否则具有多个具有适度作用的易感性等位基因的基因的净效应无法被检测到和复制。我们建议通过在AB处理途径中靶向基因来追求这一假设的科学基础设施。我们将对AB QTL进行无偏见的全基因组搜索，可能会在AB加工途径中含有新的负载基因。此外，我们将彻底搜索并检查AB处理途径已知的主要基因中其他易感性等位基因的功能。 Our specific aims are to (1) perform whole genome scans to identify novel quantitative trait loci (QTLs) linked to plasma AB levels, (2) identify novel LOAD susceptibility alleles by using multiple, large case control series to analyze the variants in conserved regions of major genes in the AB processing pathway (SORL1, APP, IDE, MME, ECE1, PLAU, BACE1, PSEN1, PSEN2, and VR22）和（3）评估特定目的2中识别的易感性等位基因的功能效应。取决于确定的每个易感性等位基因的特定位置，通过评估变体对（i）等离子体AB和/或（II）脑mRNA的影响来分析功能。我们最近的结果表明，许多敏感性等位基因可能通过改变基因表达或剪接来起作用。 有充分的证据表明，在正常老年受试者中减少AB42肽可以预防阿尔茨海默氏病（AD），这种疾病会造成对我们社会的巨大痛苦和经济损失。为了进行负担得起的预防试验并向具有可接受的风险/福利比的正常老年人施用药物，必须开发方法来识别那些处于AD风险增加的老年人。在此应用中，我们提出了实验，以识别许多具有改变AB42的变体的基因，从而影响AD风险。之所以这样做，是因为每个新的AD基因都确定了新的治疗可能性，并提高了我们识别AT风险人群的能力。