Individual Propensity to Venous Thrombosis

Summary

Principal Investigator: John Heit
Abstract: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE). We will examine both candidate genes and circulating procoagulant activity to determine if they are associated with VTE. Our specific aims are: Aim 1: To identify functional SNPs/ht- SNPs within a large set candidate genes and test these SNPs/ht-SNPs for an association with VTE. Using high throughput genotyping of known gene-centric DMAvariants (n=5000), we will test a large set of candidate genes (n=300) within the anticoagulant, procoagulant, fibrinolytic, and acute systemic inflammation pathways. Linkage dysequilibrium will be used to identify haplotype-tagging SNPs within 1,500 clinic-based, idiopathic VTE cases from the Midwest, and 1500 unrelated controls frequency-matched on patient age, gender, and county of residence;Aim 2: To determine if complex candidate gene interactions are associated with VTE. Using data from aim 1, we will apply single SNP and haplotype analyses to identify specific variants and groups of variants associated with VTE. We will also investigate the joint effects of these susceptibility genes on VTE stratified on Factor V Leiden;and Aim 3: To determine if functional assays of circulating whole blood procoagulant activity associate with VTE, including genetic interactions. We will use global functional assays to prospectively test such activity for an association with VTE in a sample of our clinic-based VTE cases (n=300) and controls (n=600), including genetic interactions. VTE is a major national health problem, with over 275,000 incident cases per year in the United States and costing over $7.3 billion (in 1999 dollars) per year for treatment charges alone. Since one-quarter of PE patients present as sudden death, the incidence of VTE must be reduced in order to improve survival. However, the incidence of VTE has remained relatively constant at about 1 per 1000 since 1980. Clearly, better methods of targeting VTE prophylaxis are needed.
Funding Period: 2005-12-01 - 2010-11-30
more information: NIH RePORT

Top Publications

  1. pmc A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q
    J A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
    J Thromb Haemost 10:1521-31. 2012
  2. pmc Procoagulant activity, but not number, of microparticles increases with age and in individuals after a single venous thromboembolism
    B A L Owen
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
    Thromb Res 127:39-46. 2011
  3. pmc The association of active cancer with venous thromboembolism location: a population-based study
    Alfonso J Tafur
    Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
    Mayo Clin Proc 86:25-30. 2011
  4. pmc Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism
    J A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine Division of Experimental Pathology, Department of Laboratory Medicine and Pathology Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
    J Thromb Haemost 9:1133-42. 2011
  5. pmc A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease
    Terri A Addona
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    Nat Biotechnol 29:635-43. 2011
  6. pmc Methodology for isolation, identification and characterization of microvesicles in peripheral blood
    Muthuvel Jayachandran
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, United States
    J Immunol Methods 375:207-14. 2012
  7. pmc Predicting the risk of venous thromboembolism recurrence
    John A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Am J Hematol 87:S63-7. 2012
  8. pmc Impact of venous thromboembolism, venous stasis syndrome, venous outflow obstruction and venous valvular incompetence on quality of life and activities of daily living: a nested case-control study
    Aneel A Ashrani
    Division of Hematology, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Vasc Med 15:387-97. 2010
  9. pmc Metabolic signatures of exercise in human plasma
    Gregory D Lewis
    Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
    Sci Transl Med 2:33ra37. 2010
  10. pmc A new data mining approach for profiling and categorizing kinetic patterns of metabolic biomarkers after myocardial injury
    Christian Baumgartner
    Research Group for Clinical Bioinformatics, Institute of Electrical, Electronic and Bioengineering, University for Health Sciences, Medical Informatics and Technology UMIT, A 6060 Hall in Tirol, Austria
    Bioinformatics 26:1745-51. 2010

Scientific Experts

  • John Heit
  • ANEEL ASHRANI
  • Christian Baumgartner
  • Muthuvel Jayachandran
  • Gregory D Lewis
  • D Chen
  • Alfonso J Tafur
  • B A L Owen
  • Terri A Addona
  • Robert E Gerszten
  • Steven A Carr
  • Oded Shaham
  • Waldemar E Wysokinski
  • Michael Burgess
  • Michael A Fifer
  • Randolph S Marks
  • Dongxiao Shen
  • Michael A Gillette
  • Hasmik Keshishian
  • Xu Shi
  • Daniel J Crusan
  • Karl R Clauser
  • Marc S Sabatine
  • W G Owen
  • Tanya M Petterson
  • Laurie A Farrell
  • D R Mani
  • Robert D McBane
  • Henna Kalsi
  • Kent R Bailey
  • A Xue
  • Ru Wei
  • Ramachandran S Vasan
  • Ravi Thadhani
  • Vamsi K Mootha
  • Catherine Ricciardi
  • Thomas J Wang

Detail Information

Publications20

  1. pmc A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q
    J A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
    J Thromb Haemost 10:1521-31. 2012
    ..To identify venous thromboembolism (VTE) disease-susceptibility genes...
  2. pmc Procoagulant activity, but not number, of microparticles increases with age and in individuals after a single venous thromboembolism
    B A L Owen
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
    Thromb Res 127:39-46. 2011
    ....
  3. pmc The association of active cancer with venous thromboembolism location: a population-based study
    Alfonso J Tafur
    Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
    Mayo Clin Proc 86:25-30. 2011
    ..To test active cancer for an association with venous thromboembolism (VTE) location...
  4. pmc Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism
    J A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine Division of Experimental Pathology, Department of Laboratory Medicine and Pathology Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
    J Thromb Haemost 9:1133-42. 2011
    ..Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action...
  5. pmc A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease
    Terri A Addona
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    Nat Biotechnol 29:635-43. 2011
    ..This study demonstrates that modern proteomic technologies, when coherently integrated, can yield novel cardiovascular biomarkers meriting further evaluation in large, heterogeneous cohorts...
  6. pmc Methodology for isolation, identification and characterization of microvesicles in peripheral blood
    Muthuvel Jayachandran
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, United States
    J Immunol Methods 375:207-14. 2012
    ..However, methods to isolate, label and quantify MV have been neither systematized nor validated...
  7. pmc Predicting the risk of venous thromboembolism recurrence
    John A Heit
    Division of Cardiovascular Diseases, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Am J Hematol 87:S63-7. 2012
    ..The appropriateness of secondary prophylaxis should be continuously reevaluated, and the prophylaxis stopped if the benefit no longer exceeds the risk...
  8. pmc Impact of venous thromboembolism, venous stasis syndrome, venous outflow obstruction and venous valvular incompetence on quality of life and activities of daily living: a nested case-control study
    Aneel A Ashrani
    Division of Hematology, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Vasc Med 15:387-97. 2010
    ..VOO and VTE are associated with impaired ADL. We hypothesize that rapid clearance of venous outflow obstruction in individuals with acute VTE will improve their QoL and ADL...
  9. pmc Metabolic signatures of exercise in human plasma
    Gregory D Lewis
    Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
    Sci Transl Med 2:33ra37. 2010
    ..Plasma metabolic profiles obtained during exercise provide signatures of exercise performance and cardiovascular disease susceptibility, in addition to highlighting molecular pathways that may modulate the salutary effects of exercise...
  10. pmc A new data mining approach for profiling and categorizing kinetic patterns of metabolic biomarkers after myocardial injury
    Christian Baumgartner
    Research Group for Clinical Bioinformatics, Institute of Electrical, Electronic and Bioengineering, University for Health Sciences, Medical Informatics and Technology UMIT, A 6060 Hall in Tirol, Austria
    Bioinformatics 26:1745-51. 2010
    ..Patients with SMI and patients undergoing catheterization without induction of myocardial infarction served as positive and negative controls to assess generalizability of markers identified in PMI...
  11. ncbi A highly-sensitive plasma von Willebrand factor ristocetin cofactor (VWF:RCo) activity assay by flow cytometry
    D Chen
    Special Coagulation Laboratory, Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Thromb Haemost 6:323-30. 2008
    ..However, current manual or automated VWF:RCo assay methods have relatively poor operating characteristics. Our goal was to develop and validate a simple, accurate, specific and sensitive platelet-based VWF:RCo assay...
  12. pmc The epidemiology of venous thromboembolism in the community
    John A Heit
    Division of Cardiovascular Diseases Section of Vascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Arterioscler Thromb Vasc Biol 28:370-2. 2008
  13. pmc Application of metabolomics to cardiovascular biomarker and pathway discovery
    Gregory D Lewis
    Center for Immunology and Inflammatory Diseases and Cardiology Division, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Am Coll Cardiol 52:117-23. 2008
    ....
  14. pmc Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity
    Oded Shaham
    Broad Institute of MIT and Harvard, Cambridge, MA, USA
    Mol Syst Biol 4:214. 2008
    ..Our findings lay the groundwork for using metabolic profiling to define an individual's 'insulin response profile', which could have value in predicting diabetes, its complications, and in guiding therapy...
  15. pmc Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury
    Gregory D Lewis
    Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
    J Clin Invest 118:3503-12. 2008
    ..Our results identify a role for metabolic profiling in the early detection of myocardial injury and suggest that similar approaches may be used for detection or prediction of other disease states...
  16. pmc Risk factors and underlying mechanisms for venous stasis syndrome: a population-based case-control study
    Aneel A Ashrani
    Division of Hematology, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Vasc Med 14:339-49. 2009
    ....