Plasma AB as a Surrogate Genetic Marker for LOAD

描述(由申请人提供)：为了了解和克服阻碍遗传关联研究复制的因素，我们最近相当详细地研究了编码胰岛素/AB降解酶基因的基因(IDE)保守区的变异。当在我们的大型病例/对照系列中进行分析时，这些变体中有相当高的比例具有适度的影响，显示出可复制的关联。基于这些结果，我们目前的工作假设是，在识别新的负荷基因方面进展缓慢，因为大多数负荷基因类似于IDE；它们具有多个易感等位基因，影响大小适中。像ApoE 4等位基因这样具有强大变异的基因的影响很容易检测到，并在小病例/对照系列中复制。但是，具有多个易感等位基因的基因的净影响虽然很小，但不能被很好地检测和复制，除非使用大型病例/对照系列来评估一组根据可能的功能影响而选择的变种。利用在上一个周期中开发的科学基础设施，我们建议通过靶向AB加工途径中的基因来追求这一假说。我们将进行一次无偏见的全基因组搜索，寻找可能在AB加工途径中含有新的负载基因的AB QTL。此外，我们还将深入寻找和研究AB加工途径中已知的主要基因中其他易感等位基因的功能。我们的具体目标是(1)进行全基因组扫描以识别与血浆AB水平相关联的新的数量性状基因座(QTL)；(2)通过使用多个大型病例对照系列来分析AB加工途径(SORL1、APP、IDE、MME、ECE1、PLAU、BACE1、PSEN1、PSEN2和VR22)中主要基因保守区的变异，来识别新的负载易感等位基因；以及(3)评估在特定目标2中识别的易感等位基因的功能效应。根据所识别的每个易感等位基因的特定位置，将通过评估该变异体对(I)血浆AB和/或(Ii)脑mRNA的影响来分析其功能。我们最近的结果表明，许多易感等位基因可能通过改变基因表达或剪接而起作用。 有强有力的证据表明，在正常的老年受试者中减少AB42肽可以预防阿尔茨海默病(AD)，这是一种给我们的社会带来巨大痛苦和经济损失的疾病。为了进行负担得起的预防试验，并以可接受的风险/收益比对正常老年人进行药物管理，必须制定方法来识别哪些老年人有更高的AD风险。在这项应用中，我们建议进行实验，以确定许多具有改变AB42从而影响AD风险的变异的基因；我们这样做是因为发现的每个新的AD基因都开启了新的治疗可能性，并提高了我们识别高危人群的能力。

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.