Clotting genetic variant, hormones and venous thrombosis

凝血遗传变异、激素和静脉血栓形成

• 批准号: 6780640
• 负责人: NICHOLAS L SMITH
• 金额: $ 59.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780640
• 关键词: antifibrinolytic agents; antithrombin III; blood coagulation; cardiovascular disorder risk; clinical research; clotting factor; drug adverse effect; estrogen inhibitor; female; gene environment interaction; gene interaction; genetic screening; genetic susceptibility; hormone therapy; human subject; medical records; oral contraceptives; patient oriented research; phlebotomy; plasminogen activator; protein C; protein S; protein glutamine gamma glutamyltransferase; sex hormones; statistics /biometry; thrombomodulin; venous thrombosis; women' s health

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.

描述（由申请人提供）：静脉血栓栓塞（VTE）通常发生在成年人中，风险在激素替代治疗（HRT），口服避孕药（OC）和选择性雌激素受体调节剂（SERMS）中增加了3倍。流行病学数据表明，促凝剂，抗凝剂和纤维蛋白水解途径的遗传变异可能会改变女性VTE的风险，尤其是在使用激素的情况下。这项研究的主要目的是鉴定12种关键凝血蛋白中的遗传变异，这些蛋白可能通过基因 - 基因相互作用以及在HRT，OC或SERM使用的存在下独立改变VTE的风险。蛋白质包括血栓形成蛋白，蛋白C，内皮蛋白C受体，蛋白S，抗凝血蛋白III，组织可激活的纤维蛋白解抑制剂（TAFI），组织纤维蛋白原激活剂（TPA）和因子VIII，VIII，IX，IX，IX，X，X和B.的二级原则， C耐药性和D-二聚体是基因相互作用和VTE风险的中间表型。这项研究的设置是Puget Sound的集团健康合作社（GHC），Puget Sound是西北太平洋的健康维护组织。这项研究是解决遗传变异对药物安全的影响（尤其是心血管终点）的影响的一部分。在18至89岁的女性中，所有住院和门诊VTE事件都发生在1995年1月1日至2007年12月31日之间。控制措施将是与年龄，高血压状况和日历年相匹配的GHC女性的随机选择。将审查病历以确定研究资格并收集V'i'E风险因素信息。将从GHC药房数据库中确定激素和SERM使用。将对存活的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结途径中关键元素的哪些单倍型修改激素或SERMS之间的关联和VTE风险。鉴定共同的遗传变异，这些变体可以独立或在存在激素或SERM的情况下增加或降低VTE风险，这将有助于告知临床医生及其女性患者有关激素使用的人身安全。