R01HL155209

Identifying Proteomics Risk Markers for Abdominal Aortic Aneurysm - Project Summary

Abdominal Aortic Aneurysm (AAA) is an important cause of morbidity and mortality in older adults. AAA rupture carries a 65% mortality rate. Currently, 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 its own risks.

Our previously funded AAA R01 project, "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 project 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. We will conduct a prospective study of proteomic risk markers for AAA (N=552 cases) over 24 years of follow-up. We will also 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. We will then compare the targeted protein levels with the aptamer-based measurements in 200 ARIC plasma samples.

(2) Conduct a genome-wide association study (GWAS) in ARIC for proteins identified and replicated in Aim 1. We will also replicate any significant genetic associations in HUNT3 (N=4,230), MESA (N=5,351), and published protein GWAS databases. Additionally, we will 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. This will be followed by a network analysis to integrate the genomic and proteomic findings.

This study will utilize the 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.

Regents Of The University Of Minnesota

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Minnesota United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 06/30/25 to 06/30/26 and the total obligations have increased 286% from $814,292 to $3,142,199.