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. 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. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BMRD (03))
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Sarkar, Rita
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University of Washington
Public Health & Prev Medicine
Schools of Public Health
United States
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Choi, Seung Hoan; Weng, Lu-Chen; Roselli, Carolina et al. (2018) Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA 320:2354-2364
Irvin, Marguerite R; Sitlani, Colleen M; Noordam, Raymond et al. (2018) Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. Pharmacogenomics J :
Lindström, Sara; Germain, Marine; Crous-Bou, Marta et al. (2017) Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. Hum Genet 136:897-902
Maloney, James P; Branchford, Brian R; Brodsky, Gary L et al. (2017) The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk. FASEB J 31:2771-2784
Harrington, L B; Marck, B T; Wiggins, K L et al. (2017) Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women. J Thromb Haemost 15:80-90
Harrington, Laura B; Weiss, Noel S; Wiggins, Kerri L et al. (2016) Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women: a population-based, case-control study. Menopause 23:143-9
Cheng, Yu-Ching; Stanne, Tara M; Giese, Anne-Katrin et al. (2016) Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. Stroke 47:307-16
Harrington, Laura B; Wiggins, Kerri L; Sitlani, Colleen M et al. (2016) The association of F11 genetic variants with the risk of incident venous thrombosis among women, by statin use. Thromb Haemost 115:682-4
Postmus, Iris; Warren, Helen R; Trompet, Stella et al. (2016) Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. J Med Genet 53:835-845
Smith, N L; Harrington, L B; Blondon, M et al. (2016) The association of statin therapy with the risk of recurrent venous thrombosis. J Thromb Haemost 14:1384-92

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