A striking finding of recent genome wide association studies (GWAS) is the consistent and diverse genome- wide significant associations of the ABO glycotransferase locus with heart and blood phenotypes. These include acute myocardial infarction (AMI), coronary artery disease, venous thrombo-embolism, as well as multiple cardiopulmonary biomarkers traits such as circulating levels of VonWillebrand factor (VWF), Factor VIII, soluble ICAM-1, soluble E-selectin, and LDL cholesterol. We have extended these findings to show nominal associations of the ABO locus with acute lung injury (ALI) and complications of obstructive sleep apnea. These data indicate an important mechanistic role for ABO glycotransferase activity and cell-specific and circulating ABO glycoprotein modifications in cardiopulmonary diseases while also underscoring an underappreciated role for complex carbohydrate modifications in diverse heart, lung, blood and sleep (HLBS) disorders. Using unbiased mass-spectrometry approaches, we propose to define, disease (AMI and ALI) and cell (platelets and endothelium) specific ABO glycoproteomes in order to develop glycopeptide markers of HLBS disease risk and cross-organ, mechanism-based phenotypes in HLBS.

Public Health Relevance

(See Instructions): Recent genomic studies reveal diverse associations of the ABO locus, encoding a glycotransferase, with heart and blood phenotypes. These include myocardial infarction, coronary artery disease and multiple cardiopulmonary biomarkers traits. We propose to define disease and cell-specific ABO glycoproteins in order to develop glycoproteomic classification and prediction across several cardiopulmonary disease traits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL108636-04
Application #
8692484
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Danthi, Narasimhan
Project Start
2011-08-20
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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