Identifying Proteomics Risk Markers for Abdominal Aortic Aneurysm

识别腹主动脉瘤的蛋白质组学风险标志物

• 批准号: 10448431
• 负责人: Weihong Tang
• 金额: $ 116.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448431
• 关键词: Abdominal Aortic Aneurysm; Adaptive Immune System; Age; Biological; Biological Assay; Biological Markers; Black Populations; Blood Vessels; Brain natriuretic peptide; Cardiac; Clinical; Data; Databases; Dyslipidemias; Elderly; Ensure; Epidemiology; Etiology; Extracellular Matrix; FGF9 gene; Fibrin fragment D; Fibrinogen; Funding; Gelatinase B; Gene Expression; Generations; Genes; Genetic Variation; Genomics; Human; Hypertension; Impairment; Individual Differences; Inflammation; Interleukin-6; International; Intervention; Light; Matrix Metalloproteinases; Measurement; Mediator of activation protein; Mendelian randomization; Morbidity - disease rate; N-terminal; Operative Surgical Procedures; Participant; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Peptide Hydrolases; Pharmacologic Substance; Plasma; Plasma Proteins; Prevention; Preventive; Primary Prevention; Prospective Studies; Proteins; Proteomics; Publishing; Reporting; Resources; Risk; Risk Factors; Risk Marker; Ruptured Abdominal Aortic Aneurysm; Sampling; Scanning; Smoker; Smoking; Subgroup; Therapeutic; Thrombin; Troponin T; Up-Regulation; Visit; aptamer; base; cardiovascular risk factor; circulating biomarkers; cohort; cytokine; follow-up; genetic association; genetic variant; genome wide association study; high risk; improved; lifetime risk; liquid chromatography mass spectrometry; male; men; middle age; mortality; never smoker; novel; population based; prospective; protein biomarkers; repaired; response; screening; sex; ultrasound

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.

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。 AAA破裂 携带≥65％的死亡率。没有针对AAA的直接药物治疗，因此 管理选项是筛查，次要风险因素干预和大型AAA的手术修复， 有风险。我们先前资助的AAA R01“确定腹部流行病学风险因素 主动脉瘤”建立 事件AAA的病因学风险因素。在15,792名ARIC参与者中，有二十多年 我们确定了665个AAA，确定了AAA的新型中年风险标志物，并估计了生命周期的风险 从45岁起的AAA为5.6％。在我们最初的R01和ARIC中持续的蛋白质组学项目的基础上，我们 提出一项为期4年的研究，以识别蛋白质组学风险标志并研究新的机制和病因 AAA的途径。我们的具体目的是：（1）利用大型基于ATAMER的血浆蛋白质组学面板 从访问2和3中的整个ARIC队列中的数据（n = 4,931种人蛋白），以进行前瞻性研究 在24年的随访中，AAA（n = 552例）的蛋白质组学风险标志物，并复制明显的蛋白质 在嵌套的AAA病例（n = 518）中鉴定出来的基于人群的Hunt3 和SCCS研究。我们将结合目标和不可知论方法。确保准确性 以及我们的发现的概括性，我们还将确定商业测定或开发针对性的定量 液相色谱 - 质谱法测定了前5名小说，重复的，基于apatameric的蛋白质和 然后将靶向蛋白水平与200个ARIC血浆样品中的基于APATMER的测量进行比较。 （2）在AIM 1中鉴定并复制的ARIC中基因组关联研究（GWAS）， 并复制Hunt3（n = 4,230），Mesa（n = 5,351）中的任何显着遗传关联，并已发表的蛋白质 GWAS数据库。我们还将进行孟德尔随机研究，编码来自 国际AAA GWAS财团（10,204 AAA和107,766个对照组），以阐明因果关系 在重要的蛋白质生物标志物和AAA之间，然后进行网络分析以整合基因组和 蛋白质组学发现。 这项研究将在ARIC和其他同类中使用无与伦比的蛋白质组学资源来确定新的风险因素和 AAA的介体对AAA预防和治疗有潜在的影响。