MUTATIONS, HORMONE THERAPY, AND VENOUS THROMBOEMBOLISM

Summary

Principal Investigator: B M Psaty
Abstract: DESCRIPTION: (Adapted from Investigator's Abstract) Epidemiologic studies have identified Factor V Leiden as the most common cause of heritable thrombophilia a prothrombotic mutation associated with a 5 to 7-fold increase in the risk of venous thromboembolism (VTE). In pre-menopausal women, the use of oral contraceptives is associated with a 4-fold increase in VTE risk, and the joint effects of oral contraceptive use and Factor V Leiden carriership increase the VTE risk of by a factor of 35 (95% IC = 8 154). Recently, the results of several observational studies and randomized clinical trials suggest that in post-menopausal women, the use of hormone replacement therapy is associated with a 3-fold increase in VTE risk. Whether post-menopausal women with prothrombotic mutations experience a similar 20-fold increase in risk when they take post-menopausal hormones remains unknown. The primary aim of this ancillary study is to assess the interaction between hormone replacement therapy and the prothrombotic mutations, Factor V Leiden and the recently described prothrombin mutation (20210A) on the incidence of VTE in a population-based case-control study conducted at Group Health Cooperative of Puget Sound (GHC). The investigators state that using a variety of computerized surveillance systems at GHC will enable them to identify both in-patient and out-patient episodes of venous thromboembolism. They anticipate recruiting 300 post-menopausal women with a first episode of objectively confirmed venous thromboembolism, and 1,200 population-based controls will be identified and recruited from the GHC enrollment files. Controls will be frequency matched to the cases on age and calendar-year. Data collection includes a review of ambulatory medical record and a telephone interview. The GHC computerized pharmacy database will be used to assess exposure to hormone replacement therapy. A venous blood specimen will be obtained from consenting subjects, processed into aliquots of white cells, plasma, and red cells, and stored at 70 degrees C prior to laboratory analysis. DNA will be extracted from white cells, and molecular genotyping assays will be conducted to assess carriership of prothrombotic mutations. Data from these various sources will be entered, linked and analyzed to address the specific aims. Under an additive model, the expected joint effects of HRT and carriership of prothrombotic mutations is 7. Compared with the null hypothesis for the additive model of a joint effect of 7, the investigators have 80% power to detect a difference between the alternative hypothesis of 18 and the null hypothesis of 7. If there is an important interaction between hormone replacement therapy and prothrombotic mutations, such a finding would offer important opportunities of VTE risk reduction by pre-treatment screening in the clinical setting for the prothrombotic mutations.
Funding Period: 1998-09-30 - 2004-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle2Group Health Research Institute, Group Health Cooperative, Seattle, Washington3Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Devel
    JAMA Intern Med 174:25-31. 2014
  2. pmc A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium
    Weihong Tang
    Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota 55454, USA
    Genet Epidemiol 37:512-21. 2013
  3. ncbi The association of smoking with venous thrombosis in women. A population-based, case-control study
    M Blondon
    University of Washington, Cardiovascular Health Research Unit, 1730 Minor Ave, Seattle, WA 98101, USA
    Thromb Haemost 109:891-6. 2013
  4. pmc Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis
    Nicholas L Smith
    Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, 1730 Minor Avenue, Seattle, WA 98101, USA
    Blood 117:6007-11. 2011
  5. pmc Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke
    Daniel A Enquobahrie
    Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA
    Am J Cardiol 101:1683-8. 2008
  6. pmc Common genetic variation in six lipid-related and statin-related genes, statin use and risk of incident nonfatal myocardial infarction and stroke
    Lucia A Hindorff
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
    Pharmacogenet Genomics 18:677-82. 2008
  7. pmc ABO genotype and risk of thrombotic events and hemorrhagic stroke
    K L Wiggins
    Department of Medicine, University of Washington, Seattle, WA 98101, USA
    J Thromb Haemost 7:263-9. 2009
  8. pmc Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke
    Rozenn N Lemaitre
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
    Atherosclerosis 204:e58-63. 2009
  9. pmc Discovering novel risk factors for venous thrombosis: a candidate-gene approach
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle, USA
    Thromb Res 123:S25-9. 2009
  10. pmc SHARE: an adaptive algorithm to select the most informative set of SNPs for candidate genetic association
    James Y Dai
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M2 C200, Seattle, WA 98109, USA
    Biostatistics 10:680-93. 2009

Scientific Experts

  • Nicholas Smith
  • K D Marciante
  • K L Wiggins
  • Wylie Burke
  • Lucia A Hindorff
  • Joshua C Bis
  • B M Psaty
  • Charles L Kooperberg
  • James Y Dai
  • Daniel A Enquobahrie
  • Rozenn N Lemaitre
  • Susan R Heckbert
  • Kenneth M Rice
  • Weihong Tang
  • M Blondon
  • Nicole L Glazer
  • Inbal Boger-Megiddo
  • Thomas Lumley
  • S R Heckbert
  • Thomas S Lumley
  • Benjamin French
  • E Oren
  • Russell P Tracy
  • Saonli Basu
  • Mariza de Andrade
  • Pierre Emmanuel Morange
  • Jacqueline C Witteman
  • Christophe Tzourio
  • Guo Li
  • Albert Hofman
  • Edwin G Bovill
  • John A Heit
  • Daan W Loth
  • Aaron R Folsom
  • David Alexandre Tregouet
  • Frank W Leebeek
  • Philippe Amouyel
  • Daniel I Chasman
  • Martina Teichert
  • Xiaoxiao Kong
  • Eric Boerwinkle
  • Jerome I Rotter
  • Sebastian M Armasu
  • B McKnight
  • Jean Charles Lambert
  • Lynda Rose
  • Guillaume Pare
  • Paul M Ridker
  • Nathan Pankratz
  • Mary Cushman
  • K M Rice
  • Andre G Uitterlinden
  • Mark Lathrop
  • James S Pankow
  • Rikje Ruiter
  • Bruno H Ch Stricker
  • Barbara McKnight
  • Eric B Larson
  • David S Siscovick
  • Joseph A C Delaney
  • Noel S Weiss
  • Curt D Furberg
  • Kenneth Rice
  • Nona Sotoodehnia
  • Leslie A Lange
  • C J M Doggen
  • Alexander P Reiner
  • Stephanie A Monks
  • R N Lemaitre

Detail Information

Publications30

  1. ncbi Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle2Group Health Research Institute, Group Health Cooperative, Seattle, Washington3Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Devel
    JAMA Intern Med 174:25-31. 2014
    ..Little is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat menopausal symptoms...
  2. pmc A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium
    Weihong Tang
    Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota 55454, USA
    Genet Epidemiol 37:512-21. 2013
    ..Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations...
  3. ncbi The association of smoking with venous thrombosis in women. A population-based, case-control study
    M Blondon
    University of Washington, Cardiovascular Health Research Unit, 1730 Minor Ave, Seattle, WA 98101, USA
    Thromb Haemost 109:891-6. 2013
    ..Our results do not support a direct biological effect of smoking on the risk of VT that is clinically relevant...
  4. pmc Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis
    Nicholas L Smith
    Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, 1730 Minor Avenue, Seattle, WA 98101, USA
    Blood 117:6007-11. 2011
    ..Both STXBP5 and VWF findings were replicated successfully. Variation in genes associated with VWF levels in the genome-wide association study was found to be independently associated with incident VT...
  5. pmc Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke
    Daniel A Enquobahrie
    Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA
    Am J Cardiol 101:1683-8. 2008
    ..77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation...
  6. pmc Common genetic variation in six lipid-related and statin-related genes, statin use and risk of incident nonfatal myocardial infarction and stroke
    Lucia A Hindorff
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
    Pharmacogenet Genomics 18:677-82. 2008
    ....
  7. pmc ABO genotype and risk of thrombotic events and hemorrhagic stroke
    K L Wiggins
    Department of Medicine, University of Washington, Seattle, WA 98101, USA
    J Thromb Haemost 7:263-9. 2009
    ..The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A(1), A(2) or B alleles is not well defined...
  8. pmc Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke
    Rozenn N Lemaitre
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
    Atherosclerosis 204:e58-63. 2009
    ..A secondary aim was to replicate the interaction of PTGS2 rs20417 (-765G to C) with aspirin use on coronary heart disease risk observed in the Atherosclerosis Risk in Communities Study (ARIC)...
  9. pmc Discovering novel risk factors for venous thrombosis: a candidate-gene approach
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle, USA
    Thromb Res 123:S25-9. 2009
    ..As an example, we present a candidate-gene approach to identify novel associations between variation in 24 clotting genes and the risk of incident venous thrombosis...
  10. pmc SHARE: an adaptive algorithm to select the most informative set of SNPs for candidate genetic association
    James Y Dai
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M2 C200, Seattle, WA 98109, USA
    Biostatistics 10:680-93. 2009
    ..Simulations and a data application show that our method has improved power over existing methodologies and that the results are informative in the search for disease-causal loci...
  11. pmc Myocardial infarction and stroke associated with diuretic based two drug antihypertensive regimens: population based case-control study
    Inbal Boger-Megiddo
    Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98101, USA
    BMJ 340:c103. 2010
    ..Design Population based case-control study. Setting Group Health Cooperative, Seattle, WA, USA...
  12. ncbi Common variation in cytochrome P450 epoxygenase genes and the risk of incident nonfatal myocardial infarction and ischemic stroke
    Kristin D Marciante
    Cardiovascular Health Research Unit, Seattle, Washington 98101, USA
    Pharmacogenet Genomics 18:535-43. 2008
    ..We conducted a population-based, case-control study at Group Health to determine whether common genetic variation in the CYP2J2, CYP2C8, and CYP2C9 genes was associated with the risk of myocardial infarction and ischemic stroke...
  13. ncbi beta1- and beta2-adrenergic receptor gene variation, beta-blocker use and risk of myocardial infarction and stroke
    Rozenn N Lemaitre
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
    Am J Hypertens 21:290-6. 2008
    ..The benefits of beta-blocker therapy may depend on underlying genetic susceptibility...
  14. ncbi Simple estimates of haplotype relative risks in case-control data
    Benjamin French
    Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98195 7232, USA
    Genet Epidemiol 30:485-94. 2006
    ..The potential for phase ambiguity does not necessarily imply uncertainty in imputed diplotypes, especially in large studies of common haplotypes...
  15. ncbi Clinical trial investigators and their prescribing patterns: another dimension to the relationship between physician investigators and the pharmaceutical industry
    Bruce M Psaty
    JAMA 295:2787-90. 2006
  16. ncbi Body mass index and the risk of venous thrombosis among postmenopausal women
    E Oren
    J Thromb Haemost 4:2273-5. 2006
  17. ncbi The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women
    N L Smith
    Department of Epidemiology, University of Washington, Seattle, WA 98101, USA
    J Thromb Haemost 4:1701-6. 2006
    ....
  18. ncbi Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle, WA, USA
    Arterioscler Thromb Vasc Biol 26:2807-12. 2006
    ..Esterified estrogen (EE), an alternative estrogenic compound, appears not to be associated with increased risk and nothing is known about the joint risk with prothrombotic genetic variants...
  19. ncbi Logic regression for analysis of the association between genetic variation in the renin-angiotensin system and myocardial infarction or stroke
    Charles Kooperberg
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    Am J Epidemiol 165:334-43. 2007
    ....
  20. ncbi Association of genetic variations with nonfatal venous thrombosis in postmenopausal women
    Nicholas L Smith
    Department of Epidemiology, University of Washington, Seattle, WA 98101, USA
    JAMA 297:489-98. 2007
    ....
  21. ncbi FDA responds to institute of medicine drug safety recommendations--in part
    Bruce M Psaty
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Center for Health Studies, Group Health, Seattle, WA 98101, USA
    JAMA 297:1917-20. 2007
  22. ncbi Renin-angiotensin system haplotypes and the risk of myocardial infarction and stroke in pharmacologically treated hypertensive patients
    Kristin D Marciante
    Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
    Am J Epidemiol 166:19-27. 2007
    ..17). In this case-control study, RAS gene haplotypes were not significantly associated with increased risks of myocardial infarction or stroke...
  23. ncbi Common VKORC1 variants are not associated with arterial or venous thrombosis
    L A Hindorff
    Department of Epidemiology, University of Washington, Seattle, WA, USA
    J Thromb Haemost 5:2025-7. 2007
  24. ncbi Personalized medicine in the era of genomics
    Wylie Burke
    Center for Genomics and Healthcare Equality and Department of Medical History and Ethics, University of Washington, Seattle, WA 98195, USA
    JAMA 298:1682-4. 2007
  25. ncbi Variation in 24 hemostatic genes and associations with non-fatal myocardial infarction and ischemic stroke
    N L Smith
    Department of Epidemiology, University of Washington, Seattle, WA, USA
    J Thromb Haemost 6:45-53. 2008
    ..We hypothesized that common variation in 24 coagulation-fibrinolysis genes would contribute to risk of incident myocardial infarction (MI) or ischemic stroke (IS)...
  26. pmc Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke
    Joshua C Bis
    Department of Medicine, University of Washington, Seattle, WA 981041, USA
    Atherosclerosis 198:166-73. 2008
    ....
  27. ncbi Recent trials in hypertension: compelling science or commercial speech?
    Bruce M Psaty
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, USA
    JAMA 295:1704-6. 2006