DNA Variants and AAA Disease

DNA 变异和 AAA 疾病

• 批准号: 8878421
• 负责人: Philip S Tsao
• 金额: $ 16.83万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878421
• 关键词: DNA; Variants; AAA; Disease

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.

描述（由申请人提供）：腹主动脉瘤（AAA）疾病是一种常见的、致死性高的疾病。先前的研究表明，这种疾病有很强的遗传因素，涉及多个位点。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进步将需要增强的风险分层工具。在斯坦福大学目前针对 AAA 疾病的血管 SCCOR 中，我们采用了数据丰富的策略来识别生物学相关的血液蛋白，这些蛋白在 AAA 疾病中提供信息。然而，血液中发现的因子（由 AAA 病变分泌）不太可能涵盖潜在病理生理过程的广度。我们建议利用腹主动脉瘤简单治疗或预防 (AAA-STOP) 试验的病例和对照的仔细表型分析来识别与 AAA 相关的新 DNA 序列变异。我们将利用下一代高通量测序技术对通过全基因组转录谱实验策略确定的候选基因进行重新测序，以构建相关的表达网络。新的错义变异将在 AAA-STOP 的第二个亚组以及表型同样良好的 AAA 患者和对照（西澳大利亚筛查研究 (WASS) 参与者）的补充组中复制。最后，经过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，以确定它们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 形成的潜在生物过程以及重要的基因-环境相互作用。因此，我们建议追求并完成以下具体目标： 1. 在 AAA-STOP 队列样本中鉴定与 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子队列进行验证基因分型。 确定罕见序列变异是否可以预测疾病进展，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，以产生用于疾病监测的有用的诊断和预后算法。此次合作提供了一个独特的机会，可以进一步利用斯坦福大学 AAA SCCOR 和 WASS 临床试验的持续成功，为患有常见且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学提供重要的见解，并指导疾病管理和未来的研究。