Clotting Genetic Variants, Hormones, and Venous Thrombosis
Condition: Cardiovascular Diseases; Thromboembolism
MeSH terms: Cardiovascular Diseases; Thromboembolism
Study type: Observational

Summary: 
      To identify genetic variants in 12 key blood clotting proteins that may modify the risk of
      venous thromboembolism in users of hormone replacement therapy.
    

Detailed description: 
      BACKGROUND:

      Venous thromboembolism (VTE) occurs commonly in adults and risk increases 3-fold among users
      of hormone replacement therapy (HRT), oral contraceptives (OC), and selective estrogen
      receptor modulators (SERMs). Epidemiologic data suggest that genetic variation in the
      pro-coagulant, anti-coagulant, and fibrinolytic pathways may modify the risk of VTE in women,
      especially in the presence of hormone use. The primary aim of this study is to identify
      genetic variants in 12 key clotting proteins that may modify the risk of VTE independently,
      through gene-gene interactions, and in the presence of HRT, OC, or SERM use. Proteins include
      thrombomodulin, protein C, endothelial protein C receptor, protein S, antithrombin III,
      tissue activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (TPA), and
      factors VIII, IX, X, and XlII A and B. Secondary aims are to determine if levels of TAFI
      antigen, TPA antigen, activated protein C resistance, and D-dimer serve as intermediate
      phenotypes for gene-drug interactions and VTE risk. The setting for this study is Group
      Health Cooperative (GHC) of Puget Sound, a health maintenance organization in the Pacific
      Northwest. This study is part of an on going, case-control study addressing the effects of
      genetic variants on drug safety, particularly cardiovascular endpoints.

      DESIGN NARRATIVE:

      The primary aim of this case-control study is to identify genetic variants in 12 key blood
      clotting proteins that may modify the risk of venous thromboembolism independently, through
      gene-gene interactions, and in the presence of hormone replacement therapy, oral
      contraceptives, or selective estrogen receptor modulators use. Proteins include
      thrombomodulin, protein C, endothelial protein C receptor, protein S, antithrombin III,
      tissue activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (TPA), and
      factors VIII, IX, X, and XlII A and B. Secondary aims of the study are to determine if levels
      of TAFI antigen, TPA antigen, activated protein C resistance, and D-dimer serve as
      intermediate phenotypes for gene-drug interactions and VTE risk. The setting for this study
      is the Group Health Cooperative (GHC) of Puget Sound, a health maintenance organization in
      the Pacific Northwest. This study is part of an on going, case-control study addressing the
      effects of genetic variants on drug safety, particularly cardiovascular endpoints.

      All inpatient and outpatient VTE events occurring between 1/1/1995 and 12/31/2007 among women
      18 to 89 years of age will be eligible for this study. Controls will be a random selection of
      women from GHC matched on age, hypertension status, and calendar year. Medical records will
      be reviewed to determine study eligibility and to collect V'i'E risk factor information.
      Hormone and SERM use will be ascertained from the GHC pharmacy database. Phlebotomy will be
      performed on surviving cases and controls to collect plasma samples and genetic information.
      Logistic regression analyses will determine which haplotypes of key elements in the clotting
      pathways modify the association between hormones or SERMSs and VTE risk. The identification
      of common genetic variants that either increase or decrease VTE risk independently or in the
      presence of hormone or SERMs will help to inform clinicians and their female patients about
      the personal safety of hormone use.

      The Seattle Program for Genomics Applications (PGA) will identify single nucleotide
      polymorphisms (SNPs) in the 12 candidate genes and use linkage disequilibrium to generate
      haplotypes. A group at the Leiden University Medical Center will perform the genotyping of
      the study population.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        General