Clotting genetic variant, hormones and venous thrombosis

描述（申请人提供）：静脉血栓栓塞（VTE）常见于成人，在激素替代疗法（HRT）、口服避孕药（OC）和选择性雌激素受体调节剂（SERM）使用者中风险增加3倍。流行病学数据表明，促凝血、抗凝和纤溶途径的遗传变异可能会改变女性发生静脉血栓栓塞的风险，尤其是在使用激素的情况下。本研究的主要目的是确定12种关键凝血蛋白的遗传变异，这些蛋白可能通过基因-基因相互作用，在HRT、OC或SERM使用的情况下独立改变VTE的风险。蛋白质包括血栓调节蛋白、蛋白质C、内皮蛋白质C受体、蛋白质S、抗凝血酶III、组织活化纤维蛋白溶解抑制剂（TAFI）、组织纤溶酶原激活剂（TPA）和因子VIII、IX、X和XIII A和B。次要目的是确定TAFI抗原、TPA抗原、活化蛋白C抗性和D-二聚体水平是否作为基因-药物相互作用和VTE风险的中间表型。这项研究的背景是普吉特海湾的团体健康合作社（GHC），这是一个位于太平洋西北部的健康维护组织。这项研究是一项正在进行的病例对照研究的一部分，该研究旨在解决遗传变异对药物安全性的影响，特别是心血管终点。1995年1月1日至2007年12月31日期间发生在18至89岁女性中的所有住院和门诊VTE事件都有资格参加本研究。对照组将从GHC中随机选择年龄、高血压状态和日历年匹配的女性。将审查病历，以确定研究资格并收集V 'i'E风险因素信息。激素和SERM的使用将从GHC药房数据库中确定。将对存活病例和对照组进行放血术，以收集血浆样本和遗传信息。逻辑回归分析将确定凝血途径中关键元件的哪些单倍型改变激素或SERMS与VTE风险之间的关联。识别独立或在激素或SERM存在的情况下增加或降低静脉血栓栓塞风险的常见遗传变异将有助于让临床医生及其女性患者了解激素使用的个人安全。

DESCRIPTION (provided by applicant): 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.