DNA Variants and AAA Disease

描述（申请人提供）：腹主动脉瘤（AAA）是一种常见、病态、高致死率的疾病。先前的研究表明，这种疾病有很强的遗传成分，涉及多个基因座。目前用于初步检测AAA存在以及确定哪些病变有快速生长/破裂风险的模式并不理想。因此，动脉瘤护理的进一步发展将需要增强风险分层工具。在我们目前斯坦福大学AAA疾病的血管SCCOR中，我们采用了一种数据丰富的策略来识别AAA疾病中具有信息的生物学相关血液蛋白。然而，在血液中发现的因子（由AAA病变分泌）不太可能捕捉到潜在病理生理过程的广度。我们建议对腹主动脉瘤-简单治疗或预防（AAA- stop）试验的病例和对照组进行仔细的表型分析，以确定与AAA相关的新的DNA序列变异。我们将利用下一代高通量测序技术对我们的实验策略鉴定的候选基因进行重测序，包括全基因组转录谱，以建立相关的表达网络。新的错义变异将在AAA- stop的第二个亚队列中进行复制，也将在同样表型良好的AAA患者和对照组（西澳大利亚筛选研究（WASS）的参与者）的补充队列中进行复制。最后，验证的序列变异将与蛋白质生物标志物和临床数据相结合，以确定其对疾病诊断和预后算法的附加价值。此外，鉴定出的罕见错义变异可能有助于深入了解调节AAA形成的潜在生物学过程以及重要的基因-环境相互作用。为此，我们建议追求和完成以下具体目标：在AAA- stop队列样本中识别与AAA疾病相关的罕见序列变异。2. 对来自AAA-STOP的第二组样本和西澳大利亚筛选研究的一个亚队列进行验证性基因分型。确定罕见序列变异是否预测疾病进展，以及它们是否添加到表型数据、蛋白质生物标志物值和相互作用项中，以产生有用的疾病监测诊断和预后算法。此次合作是一个独特的机会，可以进一步利用斯坦福AAA SCCOR和WASS临床试验的持续成功，为患有常见和危及生命的疾病的患者提供有意义的临床指南。此外，罕见变异可能会为疾病病理生物学提供重要的见解，并指导疾病管理和未来的研究。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease. Prior studies indicate a strong genetic component to the disease involving multiple loci. Present modes to initially detect the presence of AAA as well as determine which lesions are at risk for rapid growth/rupture are suboptimal. Thus, further advances in aneurysm care will require enhanced risk stratification tools. In our current Vascular SCCOR in AAA Disease at Stanford, we have employed a data-rich strategy to identify biologically relevant blood proteins that are informative in AAA disease. However, factors found in blood (secreted by AAA lesions) are unlikely to capture the breadth of the underlying pathophysiological processes. We propose to exploit the careful phenotyping of both cases and controls of the Abdominal Aortic Aneurysm-Simple Treatment or Prevention (AAA-STOP) trial to identify novel DNA sequence variants associated with AAA. We will take advantage of next-generation high-throughput sequencing technology to resequence candidate genes identified by our experimental strategy involving whole genome transcriptional profiling to build relevant expression networks. Novel missense variants will be replicated in a second subcohort of AAA-STOP as well as in a complementary cohort of equally well-phenotyped AAA patients and controls- participants of the Western Australia Screening Study (WASS). Finally, validated sequence variants will be combined with protein biomarker and clinical data to determine their additive value to disease algorithms of diagnosis and prognosis. In addition, identified rare missense variants are likely to add insight into the underlying biological processes regulating AAA formation as well as important gene-environment interactions. As such, we propose to pursue and complete the following Specific Aims: 1. to identify rare sequence variants associated with AAA disease in samples from the AAA-STOP cohort. 2. To perform validation genotyping in a second set of samples from AAA-STOP and a subcohort of the Western Australia Screening Study. To determine if rare sequence variants are predictive of disease progression and whether they add to phenotypic data, protein biomarker values, and interaction terms to produce useful diagnostic and prognostic algorithms for disease monitoring. This collaboration represents a unique opportunity to further leverage the ongoing success of the Stanford AAA SCCOR and WASS clinical trials into meaningful clinical guidelines for patients with a common and life threatening disease. In addition, rare variants will likely provide significant insight into disease pathobiology as well as guide disease management and future research.