Atherosclerotic disease is the leading cause of death, justifying continued effort to identify the determinants of this disease. Among the priorities for the NHLBI Division of Cardiovascular Diseases is the need to better characterize inherited predispositions to atherosclerosis in the context of understanding biological pathways of inflammation that could lead to biomarkers for prediction, early detection, and prognosis. The cellular adhesion pathway is one promising new avenue of research aligned with DCVD strategic goals. Although circulating adhesion protein levels predict increased risk of incident CHD and subsequent events in patients with acute coronary syndromes, existing literature focuses only on a small subset of proteins and genes comprising the adhesion pathway and thus few studies have assessed the combined effects of adhesion components. Therefore, we hypothesize that the adhesion pathway, as modeled by individual protein levels and a composite protein score, is associated with subclinical atherosclerosis. Furthermore, we hypothesize that variants in adhesion genes account for a significant portion of the variation in adhesion protein level and that these variants are associated with subclinical atherosclerosis. To test these hypotheses, we plan to expand phenotyping and genotyping of adhesion pathway components, incorporating results from previous genetic studies, including GWAS data, in the Multi-Ethnic Study of Atherosclerosis (MESA). Our three study aims are Aim 1) To test the hypothesis that the adhesion pathway is associated with subclinical atherosclerosis, we will analyze cross-sectional associations of 15 de novo adhesion protein levels and a composite adhesion protein score with subclinical atherosclerosis, Aim 2)To test the hypothesis that variants in adhesion genes account for a significant portion of the variation in adhesion protein level and that these variants are associated with subclinical atherosclerosis, we will assess the contribution of polymorphisms within genes directly connected to the measured protein with the corresponding circulating protein levels and we will analyze the association of these polymorphisms and longitudinal change of subclinical disease, and Aim 3) To replicate the strongest findings we will analyze the association of the most promising three proteins and 384 SNPs using 3,437 MESA subjects not included in Aims 1 &2. Cellular adhesion is critical in the pathophysiology of atherosclerosis and a better understanding of these mechanisms on subclinical disease may have important consequences for characterizing asymptomatic individuals and for preventing and improving care of patients with atherosclerosis. Therefore, our application expands the phenotyping and genotyping of adhesion pathway components in existing stored MESA study samples to understand the relationship of adhesion on the pathogenesis of atherosclerosis. Our ability to determine the relationships among protein levels, genetic variants, and subclinical disease in substantial numbers of subjects from four ethnic groups will greatly enhance our understanding of the roles these proteins play in the pathogenesis of disease.

Public Health Relevance

This research investigates the biological interactions and regulation of adhesion components to improve our understanding of these mechanisms on subclinical atherosclerotic disease. This application leverages existing data from the MESA Study in which the NIH has made substantial investments, with comprehensive de novo genotyping and phenotyping of the cellular adhesion pathway. The proposed multi-scale approach extends the results from GWAS and experimental studies by investigating the associations within physiological pathways where critical subclinical interactions and protein regulation takes place.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098077-02
Application #
8118113
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Hasan, Ahmed AK
Project Start
2010-08-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$710,837
Indirect Cost
$90,036
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Aaron, Carrie P; Schwartz, Joseph E; Hoffman, Eric A et al. (2018) A Longitudinal Cohort Study of Aspirin Use and Progression of Emphysema-like Lung Characteristics on CT Imaging: The MESA Lung Study. Chest 154:41-50
Balakrishnan, Poojitha; Jones, Miranda R; Vaidya, Dhananjay et al. (2018) Ethnic, Geographic, and Genetic Differences in Arsenic Metabolism at Low Arsenic Exposure: A Preliminary Analysis in the Multi-Ethnic Study of Atherosclerosis (MESA). Int J Environ Res Public Health 15:
Bell, Elizabeth J; Decker, Paul A; Tsai, Michael Y et al. (2018) Hepatocyte growth factor is associated with progression of atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 272:162-167
Bielinski, Suzette J; Berardi, Cecilia; Decker, Paul A et al. (2017) Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease. Heart 103:1185-1193
Avery, Christy L; Wassel, Christina L; Richard, Melissa A et al. (2017) Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. Heart Rhythm 14:572-580
Yoneyama, S; Yao, J; Guo, X et al. (2017) Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. Int J Obes (Lond) 41:324-331
Pike, Mindy M; Larson, Nicholas B; Wassel, Christina L et al. (2017) ABO blood group is associated with peripheral arterial disease in African Americans: The Multi-Ethnic Study of Atherosclerosis (MESA). Thromb Res 153:1-6
Berardi, Cecilia; Wassel, Christine L; Decker, Paul A et al. (2017) Elevated Levels of Adhesion Proteins Are Associated With Low Ankle-Brachial Index. Angiology 68:322-329
Steffen, Brian T; Bielinski, Suzette J; Decker, Paul A et al. (2017) Low high-density lipoprotein cholesterol and particle concentrations are associated with greater levels of endothelial activation markers in Multi-Ethnic Study of Atherosclerosis participants. J Clin Lipidol 11:955-963.e3
Larson, Nicholas B; Bell, Elizabeth J; Decker, Paul A et al. (2016) ABO blood group associations with markers of endothelial dysfunction in the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 251:422-429

Showing the most recent 10 out of 26 publications