Plasma AB as a Surrogate Genetic Marker for LOAD

描述（由申请人提供）：为了理解和克服阻碍遗传关联研究复制的因素，我们最近非常详细地研究了编码胰岛素/AB 降解酶基因的基因 (IDE) 保守区域的变异。这些变异中很大一部分具有适度的影响，在我们的大型病例/对照系列中进行分析时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，识别新的 LOAD 基因的进展缓慢，因为大多数 LOAD 基因类似于 IDE；它们具有多种易感性等位基因，且效应大小适中。具有强大变异（如 ApoE 4 等位基因）的基因的作用很容易在小病例/对照系列中检测和复制。但是，具有多个易感性等位基因的基因的净效应虽然影响不大，但无法很好地检测和复制，除非采用大型病例/对照系列来评估为其可能的功能效应而选择的一组变体。利用上一个周期开发的科学基础设施，我们建议通过针对 AB 加工途径中的基因来追求这一假设。我们将对可能在 AB 加工途径中包含新 LOAD 基因的 AB QTL 进行公正的全基因组搜索。此外，我们将彻底搜索并检查 AB 加工途径已知主要基因中其他易感性等位基因的功能。我们的具体目标是 (1) 进行全基因组扫描，以确定与血浆 AB 水平相关的新数量性状位点 (QTL)，(2) 通过使用多个大型病例对照系列来分析 AB 加工途径中主要基因的保守区域（SORL1、APP、IDE、MME、ECE1、PLAU、BACE1、PSEN1、PSEN2 和 VR22）中的变异，确定新的 LOAD 易感性等位基因，以及 (3) 评估功能效果特定目标 2 中确定的易感性等位基因的数量。根据确定的每个易感性等位基因的具体位置，将通过评估变体对 (i) 血浆 AB 和/或 (ii) 脑 mRNA 的影响来分析功能。我们最近的结果表明，许多易感性等位基因可能通过改变基因表达或剪接发挥作用。 有强有力的证据表明，减少正常老年人体内的 AB42 肽可以预防阿尔茨海默病 (AD)，这种疾病给我们的社会带来巨大的痛苦和经济损失。为了进行负担得起的预防试验并以可接受的风险/效益比向正常老年人给药，必须制定方法来识别 AD 风险较高的老年人。在此应用中，我们建议通过实验来鉴定许多具有改变 AB42 从而影响 AD 风险的基因变异；我们这样做是因为每个新发现的 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.