Identifying Proteomics Risk Markers for Abdominal Aortic Aneurysm

项目摘要 腹主动脉瘤(AAA)是老年人发病率和死亡率的重要原因。腹主动脉破裂 ≥的死亡率为65%。目前还没有针对AAA的直接药物治疗，因此主要的 管理选项包括筛查、二次危险因素干预和大型AAA的手术修复， 这是有风险的。我们先前资助的AAA R01《确定腹部疾病的流行病学危险因素》 “主动脉瘤”是美国为数不多的几个基于人群的前瞻性队列研究之一。 AAA事件的病因危险因素。在对15,792名ARIC参与者进行了20多年的跟踪调查后， 我们确定了665个AAA，确定了AAA的新的中年风险标记物，并估计了 从45岁起AAA为5.6%。在我们最初的R01和ARIC正在进行的蛋白质组项目的基础上，我们 提出一项为期4年的研究，以确定蛋白质组学风险标记并研究新的机制和病因学 AAA的路径。我们的具体目标是：(1)利用一大批基于适体的血浆蛋白质组学 来自访问2和访问3的整个ARIC队列中的数据(n=4,931个人类蛋白质)，以进行前瞻性研究 AAA(n=552例)的蛋白质组学风险标记物24年随访，并复制重要蛋白质 在嵌套AAA病例(n=518)-队列(n=833)样本中发现，这些样本来自基于人群的HUNT3 和SCCS研究。我们将使用目标明确和不可知论相结合的方法。为了保证准确度， 对于我们的研究结果的普遍性，我们还将确定商业分析或开发有针对性的定量 液相色谱-质谱法分析前5种新的、复制的、基于适配子的蛋白质和 然后将200个ARIC血浆样本的目标蛋白质水平与基于适体的测量结果进行比较。 (2)在ARIC中对在AIM 1中识别和复制的蛋白质进行全基因组关联研究， 并复制HUNT3(n=4,230)、MESA(n=5,351)和已发表的蛋白质中任何显著的遗传关联 Gwas数据库。我们还将进行孟德尔随机化研究，纳入来自 国际AAA GWAS联盟(10,204个AAA和107,766个对照)，以阐明因果关系 在重要的蛋白质生物标记物和AAA之间，随后进行网络分析以整合基因组和 蛋白质组学的发现。 这项研究将利用ARIC和其他队列中无与伦比的蛋白质组资源来识别新的危险因素和 AAA的介体，对AAA的预防和治疗具有潜在的影响。

Project Summary Abdominal aortic aneurysm (AAA) is an important cause of morbidity and mortality in older adults. AAA rupture carries a ≥ 65% mortality rate. There are no direct pharmaceutical treatments for AAA, so the main management options are screening, secondary risk factor intervention, and surgical repair for large AAAs, which carries risk. Our previously funded AAA R01 “Identifying Epidemiological Risk Factors for Abdominal Aortic Aneurysm” established one of the few large population-based prospective US cohorts to identify etiologic risk factors for incident AAA. Among 15,792 ARIC participants followed for more than two decades, we ascertained 665 AAAs, identified novel middle-age risk markers for AAA, and estimated the lifetime risk for AAA from age 45 to be 5.6%. Building upon our original R01 and an ongoing proteomic project in ARIC, we propose a 4-year study to identify proteomics risk markers and investigate novel mechanisms and etiological pathways for AAA. Our specific aims are to: (1) Leverage a large panel of aptamer-based, plasma proteomics data (n=4,931 human proteins) in the entire ARIC cohort from Visits 2 and 3, to conduct a prospective study of proteomic risk markers for AAA (n=552 cases) over 24 years of follow-up, and to replicate significant proteins identified in nested AAA case (n=518)-cohort (n=833) samples from the prospective, population-based HUNT3 and SCCS studies. We will use a combination of targeted and agnostic approaches. To ensure the accuracy and generalizability of our findings, we will also identify commercial assays or develop targeted quantitative liquid chromatography-mass spectrometry assays for the top 5 novel, replicated, aptameric-based proteins and then compare the targeted protein levels with the aptamer-based measurements in 200 ARIC plasma samples. (2) Conduct genome-wide association study (GWAS) in ARIC for proteins identified and replicated in Aim 1, and replicate any significant genetic associations in HUNT3 (n=4,230), MESA (n=5,351), and published protein GWAS database. We will also conduct a Mendelian randomization study, incorporating data from the international AAA GWAS Consortium (10,204 AAAs and 107,766 controls), to elucidate the causal relation between significant protein biomarkers and AAA, followed by a network analysis to integrate the genomic and proteomic findings. This study will use unsurpassed proteomic resource in ARIC and other cohorts to identify new risk factors and mediators of AAA, with potential implications for AAA prevention and treatment.