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 #
5U01HL108636-02
Application #
8322513
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Larkin, Jennie E
Project Start
2011-08-20
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$610,070
Indirect Cost
$228,776
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hu, Yu; Liu, Yichuan; Mao, Xianyun et al. (2014) PennSeq: accurate isoform-specific gene expression quantification in RNA-Seq by modeling non-uniform read distribution. Nucleic Acids Res 42:e20
Reilly, John P; Meyer, Nuala J; Shashaty, Michael G S et al. (2014) ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis. Chest 145:753-61
Ferguson, Jane F; Mulvey, Claire K; Patel, Parth N et al. (2014) Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers. Mol Nutr Food Res 58:601-13
McGillicuddy, Fiona C; Moll, Herwig P; Farouk, Samira et al. (2014) Translational studies of A20 in atherosclerosis and cardiovascular disease. Adv Exp Med Biol 809:83-101
O'Neill, S M; Hinkle, C; Chen, S-J et al. (2014) Targeting adipose tissue via systemic gene therapy. Gene Ther 21:653-61
Liu, Yichuan; Ferguson, Jane F; Xue, Chenyi et al. (2014) Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases. Arterioscler Thromb Vasc Biol 34:902-12
Ferguson, J F; Ryan, M F; Gibney, E R et al. (2014) Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers. Nutr Metab Cardiovasc Dis 24:996-1003
Zhang, Hanrui; Reilly, Muredach P (2014) Anti-inflammatory effects of high-density lipoprotein through activating transcription factor 3: benefit beyond cholesterol transport-dependent processes. Arterioscler Thromb Vasc Biol 34:e11-2
Wojczynski, Mary K; Li, Mingyao; Bielak, Lawrence F et al. (2013) Genetics of coronary artery calcification among African Americans, a meta-analysis. BMC Med Genet 14:75
Foulkes, Andrea S; Matthews, Gregory J; Das, Ujjwal et al. (2013) Mixed modeling of meta-analysis P-values (MixMAP) suggests multiple novel gene loci for low density lipoprotein cholesterol. PLoS One 8:e54812

Showing the most recent 10 out of 14 publications