THROMBOTIC, INFLAMMATORY & GENE MARKERS OF CVD IN WOMEN

Summary

Principal Investigator: Paul Ridker
Abstract: DESCRIPTION: (Adapted from Investigator's Abstract) Prospective data derived almost exclusively from men indicate that several plasma and genetic markers of thrombosis exist and that affected individuals are at markedly increased risk of future myocardial infarction (MI). However, data describing novel markers for coronary thrombosis among women are scant. The investigators therefore propose to comprehensively evaluate a series of thrombotic, inflammatory, and genetic markers for MI among participants in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort study of over 90,000 ethnically representative post-menopausal American women aged 50-79 years. Employing a prospective nested case-control design, they will assay baseline plasma and buffy coat samples for nine markers of increased thrombotic potential (tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), total plasma homocysteine, prothrombin fragment F1+2, D-dimer, APC-R, C-reactive protein, interleukin-6, and sICAM-1) to determine whether elevations of these parameters lead to future MI or coronary death. They will also explore common genetic polymorphisms in the tPA, PAI-1, MTHFR, thrombomodulin, prothrombin, and factor V genes so that both inherited and environmental determinants of coronary thrombosis in women can simultaneously be evaluated. Case subjects will be WHI-OS participants who were free of cardiovascular disease at study entry and subsequently developed a documented MI or coronary death during follow-up (N = 650). Control subjects will be selected from study participants who remained free of disease during follow-up; controls will be 1:1 matched to cases by age, smoking status, ethnicity, and follow-up time. Data on usual risk factors, hormone replacement therapy, and standard lipid profiles will be used to evaluate for potential confounding and effect modification. The investigators note that the analyses will take advantage of a unique and unprecedented blood bank from a well-characterized, ethnically diverse, large-scale cohort of post-menopausal women with ongoing follow-up and high quality endpoint verification, thereby providing an efficient way to critically evaluate the hypothesized roles of hemostasis thrombosis and inflammation as risk factors for future MI and coronary death among American women.
Funding Period: 1999-09-01 - 2004-08-31
more information: NIH RePORT

Top Publications

  1. pmc Psychosocial effects of physical and verbal abuse in postmenopausal women
    Charles P Mouton
    Department of Community and Family Medicine, Howard University College of Medicine, 520 W Street NW, Washington, DC 20059, USA
    Ann Fam Med 8:206-13. 2010
  2. ncbi A prospective replication study of five gene variants previously associated with risk of myocardial infarction
    R Y L Zee
    J Thromb Haemost 4:2093-5. 2006
  3. ncbi Association of adiponectin gene variations with risk of incident myocardial infarction and ischemic stroke: a nested case-control study
    Hillary H Hegener
    Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Clin Chem 52:2021-7. 2006
  4. ncbi Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events
    Michelle A Albert
    Center for Cardiovascular Disease Prevention and Division of Cardiovascular Diseases, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Circulation 114:2619-26. 2006
  5. pmc Differential effect of soluble intercellular adhesion molecule-1 on the progression of atherosclerosis as compared to arterial thrombosis: a prospective analysis of the Women's Health Study
    Michelle A Albert
    Center for Cardiovascular Disease Prevention, Donald W Reynolds Center for Cardiovascular Disease Research, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Atherosclerosis 197:297-302. 2008
  6. ncbi Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism
    Robert Y L Zee
    Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medial School, 900 CommonwealthAvenue East, Boston, MA 02215, USA
    Atherosclerosis 197:694-9. 2008
  7. ncbi Two common gene variants on chromosome 9 and risk of atherothrombosis
    Robert Y L Zee
    Stroke 38:e111. 2007
  8. pmc Genetic variants within the interleukin-1 gene cluster, and risk of incident myocardial infarction, and ischemic stroke: a nested case-control approach
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, The Donald W Reynolds Center for Cardiovascular Research, The Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 022215, USA
    Atherosclerosis 201:124-9. 2008
  9. ncbi Genetic variants of tumor necrosis factor superfamily, member 4 (TNFSF4), and risk of incident atherothrombosis and venous thromboembolism
    Anders Malarstig
    Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Clin Chem 54:833-40. 2008
  10. pmc A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients
    Xingyu Wang
    Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China
    Stroke 40:683-95. 2009

Scientific Experts

  • Charles P Mouton
  • Robert D Langer
  • R Y Zee
  • Michelle Asha Albert
  • Paul M Ridker
  • Nancy R Cook
  • Xingyu Wang
  • Anders Malarstig
  • H H Hegener
  • Hillary H Hegener
  • Piotr Kozlowski
  • P M Ridker
  • D T Miller
  • Li Yung Lui
  • Andrea M Johnson
  • Lisheng Liu
  • Wolfgang Lalouschek
  • Warren S Browner
  • Suzanne Cheng
  • Christine Mannhalter
  • Christof Kessler
  • Steve R Cummings
  • Florian Stoegbauer
  • Brian K Rhees
  • Klaus Berger
  • Harald Funke
  • Georg Endler
  • Klaus Lindpaintner
  • Jan Luedemann
  • Yu Shi
  • Henry A Erlich
  • Stefan Greisenegger
  • Nancy Cook
  • Victoria H Brophy
  • E Bernd Ringelstein
  • Kirsti A Diehl
  • Per Eriksson
  • Lynda Rose
  • Anders Hamsten
  • T Kurth
  • Jacqueline Suk Danik
  • I Min Lee
  • J M Gaziano
  • Ross Lazarus
  • Daniel I Chasman
  • David T Miller
  • K A Diehl
  • David J Kwiatkowski
  • R Lazarus
  • N R Cook
  • J Suk Danik
  • D J Kwiatkowski
  • P Kozlowski
  • D I Chasman

Detail Information

Publications24

  1. pmc Psychosocial effects of physical and verbal abuse in postmenopausal women
    Charles P Mouton
    Department of Community and Family Medicine, Howard University College of Medicine, 520 W Street NW, Washington, DC 20059, USA
    Ann Fam Med 8:206-13. 2010
    ..The purpose of this study was to examine the psychological effects of physical and verbal abuse in a cohort of older women...
  2. ncbi A prospective replication study of five gene variants previously associated with risk of myocardial infarction
    R Y L Zee
    J Thromb Haemost 4:2093-5. 2006
  3. ncbi Association of adiponectin gene variations with risk of incident myocardial infarction and ischemic stroke: a nested case-control study
    Hillary H Hegener
    Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Clin Chem 52:2021-7. 2006
    ..No prospective data are available, however, on the risk of atherothrombotic disorders in persons with ADIPOQ variations who do not have diabetes...
  4. ncbi Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events
    Michelle A Albert
    Center for Cardiovascular Disease Prevention and Division of Cardiovascular Diseases, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Circulation 114:2619-26. 2006
    ..Virtually no data are available that examine the prospective association between novel inflammatory and hemostatic CVD risk indicators, socioeconomic status, and incident CVD events...
  5. pmc Differential effect of soluble intercellular adhesion molecule-1 on the progression of atherosclerosis as compared to arterial thrombosis: a prospective analysis of the Women's Health Study
    Michelle A Albert
    Center for Cardiovascular Disease Prevention, Donald W Reynolds Center for Cardiovascular Disease Research, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Atherosclerosis 197:297-302. 2008
    ....
  6. ncbi Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism
    Robert Y L Zee
    Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medial School, 900 CommonwealthAvenue East, Boston, MA 02215, USA
    Atherosclerosis 197:694-9. 2008
    ..The present investigation provides evidence for an association of the P2RY12 haplotype H2 with lower risk of DVT/PE; however these findings require replication in other well-designed studies...
  7. ncbi Two common gene variants on chromosome 9 and risk of atherothrombosis
    Robert Y L Zee
    Stroke 38:e111. 2007
  8. pmc Genetic variants within the interleukin-1 gene cluster, and risk of incident myocardial infarction, and ischemic stroke: a nested case-control approach
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, The Donald W Reynolds Center for Cardiovascular Research, The Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 022215, USA
    Atherosclerosis 201:124-9. 2008
    ..However, to date, no prospective, genetic-epidemiological data are available...
  9. ncbi Genetic variants of tumor necrosis factor superfamily, member 4 (TNFSF4), and risk of incident atherothrombosis and venous thromboembolism
    Anders Malarstig
    Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Clin Chem 54:833-40. 2008
    ..Recent data have implicated tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4) gene variation in myocardial infarction in women; however, no prospective data are available on either incident arterial or venous disorders...
  10. pmc A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients
    Xingyu Wang
    Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China
    Stroke 40:683-95. 2009
    ....
  11. pmc Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, United States
    Clin Chim Acta 403:139-41. 2009
    ..Recent data have implicated telomere length shortening as a potential risk predictor for cardiovascular disease. However, to date, prospective epidemiological data are scarce...
  12. ncbi Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levels
    Piotr Kozlowski
    Division of Hematology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Ann Hum Genet 70:574-86. 2006
    ....
  13. ncbi Polymorphisms of prostaglandin-endoperoxide synthase 2 gene, and prostaglandin-E receptor 2 gene, C-reactive protein concentrations and risk of atherothrombosis: a nested case-control approach
    H H Hegener
    Center for Cardiovascular Disease Prevention, The Donald W Reynolds Center for Cardiovascular Research, The Leducq Center for Molecular and Genetic Epidemiology, Boston, MA 02215, USA
    J Thromb Haemost 4:1718-22. 2006
    ..Recent data have shown an association between polymorphisms of prostaglandin-endoperoxide synthase-2 gene (PTGS2; alias COX-2), and prostaglandin-E receptor-2 gene (PTGER2) and risk of atherothrombotic disorders...
  14. ncbi Tryptophanyl-tRNA synthetase gene polymorphisms and risk of incident myocardial infarction
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, The LeDucq Center for Cardiovascular Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Atherosclerosis 181:137-41. 2005
    ..In conclusion, we found no evidence for an association between the common polymorphisms or haplotypes of the tryptophanyl-tRNA synthetase gene tested and risk of myocardial infarction...
  15. ncbi Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease. The Women's Health Initiative Observational Study
    Robert D Langer
    Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0978, La Jolla, CA 92093 0978, USA
    Thromb Haemost 93:1108-16. 2005
    ..Some associations differed between women with and without incident CHD, especially for EP, where inflammatory and thrombotic markers were higher in cases. These associations remain speculative pending confirmation in randomized trials...
  16. ncbi Complement factor H Y402H gene polymorphism, C-reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: a nested case-control study
    Robert Y L Zee
    Laboratory of Genetic Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA
    Atherosclerosis 187:332-5. 2006
    ..An exonic polymorphism (Y402H) in the complement factor H (CFH) gene, which locates within the binding sites for heparin and C-reactive protein, has recently been described and hypothesized to play an important role in atherothrombosis...
  17. ncbi Association of common CRP gene variants with CRP levels and cardiovascular events
    D T Miller
    Division of Hematology, Brigham and Women s Hospital, 75 Francis Street, Boston, MA 02115, USA
    Ann Hum Genet 69:623-38. 2005
    ..001). Taken together, these data imply significant interactions between both genetic and environmental contributions to the increased CRP levels that predict a greater risk of future atherothrombotic events in epidemiological studies...
  18. ncbi Carboxypeptidase B2 gene polymorphisms and the risk of venous thromboembolism
    R Y L Zee
    J Thromb Haemost 3:2819-21. 2005
  19. ncbi Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis
    R Y L Zee
    Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, MA 02215, USA
    J Thromb Haemost 4:341-8. 2006
    ..Polymorphisms in candidate genes related to lipid metabolism, thrombosis, hemostasis, cell-matrix adhesion, and inflammation have been suggested clinically useful in risk assessment of cardiovascular disease...
  20. ncbi Polymorphism in the beta2-adrenergic receptor and lipoprotein lipase genes as risk determinants for idiopathic venous thromboembolism: a multilocus, population-based, prospective genetic analysis
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Circulation 113:2193-200. 2006
    ..Candidate genes in inflammation, thrombosis, coagulation, and lipid metabolism pathways have been implicated in venous thromboembolism (VTE)...
  21. ncbi Polymorphisms in the advanced glycosylation end product-specific receptor gene and risk of incident myocardial infarction or ischemic stroke
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, The Donald W Reynolds Center for Cardiovascular Research, The Leducq Center for Molecular and Genetic Epidemiology, Boston, Mass, USA
    Stroke 37:1686-90. 2006
    ..However, to date, no genetic-epidemiological data are available on risk of atherothrombotic events among nondiabetic populations...
  22. ncbi Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach
    Robert Y L Zee
    Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, 900 Commonwealth Ave East, Boston, Massachusetts 02215, USA
    Stroke 37:2007-11. 2006
    ..Recent findings have implicated specific gene polymorphisms of arachidonate 5-lipoxygenase-activating protein (ALOX5AP), and 2 at-risk haplotypes (HapA, HapB) in myocardial infarction and stroke. To date, no prospective data are available...
  23. ncbi Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation
    Robert Y L Zee
    Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, Massachusetts 02215, USA
    Stroke 37:2012-7. 2006
    ..Case-control studies in other populations have yielded mixed evidence for association. A recent analysis in a prospective, non-Icelandic study found an association with stroke after stratification by hypertension...
  24. pmc Haplotype analysis of the beta2 adrenergic receptor gene and risk of myocardial infarction in humans
    Robert Y L Zee
    Center for Cardiovascular Disease Prevention, LeDucq Center for Molecular and Genetic Epidemiology, Harvard Medical School, Boston, Massachusetts 02215, USA
    Genetics 169:1583-7. 2005
    ..In conclusion, variation in haplotype frequencies for the beta2 adrenergic receptor gene was found to be associated with risk of myocardial infarction...