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: 10295903
• 负责人: Weihong Tang
• 金额: $ 81.43万
• 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/10295903
• 关键词: Abdominal Aortic Aneurysm; Adaptive Immune System; Age; Biological; Biological Assay; Biological Markers; 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; Ultrasonography; 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

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.

项目总结