Abnormalities in the plasminogen activator system have been implicated in the pathogenesis of arterial and cerebral thrombosis. In particular, elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), and t-PA/PAI-1 complexes have been found to correlate with increased risk of myocardial infarction (MI) and/or stroke. Vascular fibrinolytic balance is, to a large part, determined by the competing effects of t-PA and PAI-1, and reflects a complex interplay between genetic and environmental factors. The present collaboration focuses on the common hypothesis that the association between activation of the renin-angiotensin- aldosterone system (RAAS) and atherothrombotic events derives from an interaction between the RAAS and the fibrinolytic system. The collaborative team that we have assembled to test this hypothesis includes investigators from 3 continents (America, Europe, and Africa), from 5 academic institutions (Meharry Medical College, Vanderbilt University Medical School, University of Groningen, University of Michigan and University of Ghana) and from multiple departments within these institutions. The individual investigators bring to this collaboration diverse and complementary skills in molecular biology, vascular biology, hypothesis-driven patient-oriented research, human genetics, and clinical and genetic epidemiology. The proposal is comprised of 4 complementary projects: 1) Molecular Genetics of PAI-1 Expression, 2) Genes and Fibrinolytic Capacity of Human Endothelium, 3) Genetic Architecture of Plasma t-PA and PAI-1, and 4) Genetic Variants and Thrombosis: The Renin-Angiotensin and Fibrinolytic Systems. The proposed molecular genetic methods, new transgenic mouse models, mechanistic human studies, and innovative study designs in genetic epidemiology promise to provide complementary data. Data derived from these studies are expected yield new information regarding the mechanism of interaction of the RAAS and fibrinolytic systems. The collaboration takes advantage of existing DNA samples collected from American, European, and African population studies and intervention trials to test the hypothesis in groups of different ethnic background and cardiovascular risk. These population- based studies are expected to generate new hypotheses to be tested at the molecular level in cells and at a physiological level in humans. This collaborative proposal provides a robust mechanism for highly focused translational research in the molecular genetics and biology of the role of the fibrinolytic system in arterial and cerebral thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067466-02
Application #
6391001
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Ganguly, Pankaj
Project Start
2000-09-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$218,580
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101
Huang, Jie; Sabater-Lleal, Maria; Asselbergs, Folkert W et al. (2012) Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood 120:4873-81
Boraska, Vesna; Jeron?i?, Ana; Colonna, Vincenza et al. (2012) Genome-wide meta-analysis of common variant differences between men and women. Hum Mol Genet 21:4805-15
Bentley, John P; Asselbergs, Folkert W; Coffey, Christopher S et al. (2010) Cardiovascular risk associated with interactions among polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems. PLoS One 5:e12757
Asselbergs, Folkert W; Pattin, Kristine; Snieder, Harold et al. (2008) Genetic architecture of tissue-type plasminogen activator and plasminogen activator inhibitor-1. Semin Thromb Hemost 34:562-8
Asselbergs, Folkert W; Williams, Scott M; Hebert, Patricia R et al. (2007) The effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context. Hum Genet 122:275-81
Asselbergs, F W; Williams, S M; Hebert, P R et al. (2007) Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits. J Thromb Haemost 5:313-20
Asselbergs, Folkert W; Williams, Scott M; Hebert, Patricia R et al. (2007) Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels. Genomics 89:362-9
Asselbergs, Folkert W; Williams, Scott M; Hebert, Patricia R et al. (2006) The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels. Thromb Haemost 96:471-7
Coffey, Christopher S; Hebert, Patricia R; Ritchie, Marylyn D et al. (2004) An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene interactions on risk of myocardial infarction: the importance of model validation. BMC Bioinformatics 5:49

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