Identifying Proteomics Risk Markers for Abdominal Aortic Aneurysm

项目摘要 腹主动脉瘤（AAA）是老年人发病和死亡的重要原因。AAA破裂 死亡率≥ 65% AAA没有直接的药物治疗，所以主要的治疗方法是 管理选项是筛查、次要风险因素干预和大型AAA的手术修复， 这是有风险的我们先前资助的AAA R 01“确定腹部疾病的流行病学风险因素” 主动脉瘤”建立了为数不多的基于人群的前瞻性美国队列，以确定 AAA事件的病因风险因素。在15,792名ARIC参与者中， 我们确定了665例AAA，确定了AAA的新的中年风险标志物，并估计了AAA的终身风险。 AAA从45岁起为5.6%。基于我们最初的R 01和ARIC正在进行的蛋白质组学项目，我们 提出一项为期4年的研究，以确定蛋白质组学风险标志物，并调查新的机制和病因 AAA的路径。我们的具体目标是：（1）利用大量基于适体的血浆蛋白质组学 来自访视2和3的整个ARIC队列中的数据（n= 4，931种人蛋白），以进行一项前瞻性研究， AAA的蛋白质组学风险标志物（n=552例病例）超过24年的随访，并复制重要蛋白质 在来自前瞻性、基于人群的HUNT 3的嵌套AAA病例（n=518）-队列（n=833）样本中确定 SCCS研究。我们将使用有针对性的和不可知的方法相结合。已经力求准确 和我们的研究结果的普遍性，我们还将确定商业测定或开发有针对性的定量 前5种新型、可复制、基于适体的蛋白质的液相色谱-质谱分析， 然后将200个ARIC血浆样本中的靶蛋白水平与基于适体的测量值进行比较。 (2)在ARIC中对目标1中鉴定和复制的蛋白质进行全基因组关联研究（GWAS）， 并在HUNT 3（n= 4，230）、梅萨（n= 5，351）和已发表的蛋白质中复制任何显著的遗传关联。 GWAS数据库。我们还将进行一项孟德尔随机化研究，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 重要的蛋白质生物标志物和AAA之间的关系，然后进行网络分析，以整合基因组和 蛋白质组学发现 这项研究将使用ARIC和其他队列中无与伦比的蛋白质组资源来识别新的风险因素， AAA的介质，对AAA的预防和治疗具有潜在的意义。

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.