Clotting genetic variant, hormones and venous thrombosis

描述（由申请人提供）：静脉血栓栓塞（VTE）常见于成人，使用激素替代疗法（HRT）、口服避孕药（OC）和选择性雌激素受体调节剂（SERMs）的患者风险增加3倍。流行病学数据表明，促凝、抗凝和纤溶途径的遗传变异可能改变女性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鉴定12个关键凝血蛋白的基因变异，这些基因变异可能通过基因-基因相互作用以及HRT、OC或SERM的使用独立地改变静脉血栓栓塞的风险。蛋白质包括血栓调节蛋白、蛋白C、内皮蛋白C受体、蛋白S、抗凝血酶III、组织可活化纤维蛋白溶解抑制剂（TAFI）、组织纤溶酶原激活剂（TPA）以及因子VIII、IX、X和XlII 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-药物相互作用和静脉血栓栓塞风险的中间表型。本研究的背景是太平洋西北地区普吉特湾的一个健康维护组织——团体健康合作社（GHC）。本研究是一项正在进行的病例对照研究的一部分，研究基因变异对药物安全性的影响，特别是心血管终点。在1995年1月1日至2007年12月31日期间发生的所有住院和门诊静脉血栓栓塞事件，年龄在18至89岁之间的女性都将符合本研究的条件。对照将从年龄、高血压状况和日历年匹配的GHC中随机选择妇女。将审查医疗记录，以确定研究资格，并收集V 'E风险因素信息。激素和SERM的使用将从GHC药房数据库确定。将对存活病例和对照组进行静脉切开术，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哪些关键元素的单倍型改变了激素或SERMSs与静脉血栓栓塞风险之间的关系。识别单独增加或减少静脉血栓栓塞风险或存在激素或serm的常见遗传变异将有助于告知临床医生及其女性患者激素使用的个人安全性。

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.