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) 在成人中常见，并且在激素替代疗法 (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、抗凝血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，特别是在使用激素的情况下。本研究的主要目的是鉴定 12 种关键凝血蛋白的遗传变异，这些变异可能通过基因-基因相互作用，在使用 HRT、OC​​ 或 SERM 的情况下独立改变 VTE 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、组织可激活纤溶抑制剂 (TAFI)、组织纤溶酶原激活剂 (TPA) 以及因子 VIII、IX、X 和 XlII A 和 B。次要目标是确定 TAFI 抗原、TPA 抗原、活化蛋白 C 抗性和 D-二聚体的水平是否作为基因-药物相互作用和 VTE 的中间表型 风险。本研究的背景是普吉特海湾的团体健康合作社 (GHC)，这是太平洋西北地区的一个健康维护组织。这项研究是一项正在进行的病例对照研究的一部分，该研究旨在探讨基因变异对药物安全性（特别是心血管终点）的影响。 1995 年 1 月 1 日至 2007 年 12 月 31 日期间，18 至 89 岁女性中发生的所有住院和门诊 VTE 事件均符合本研究的资格。对照将是从 GHC 中随机选择的女性，这些女性的年龄、高血压状况和日历年份都相匹配。将审查医疗记录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。将对幸存病例和对照进行放血，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素的哪些单倍型会改变激素或 SERMS 与 VTE 风险之间的关联。识别单独或在激素或 SERM 存在的情况下增加或降低 VTE 风险的常见遗传变异将有助于告知临床医生及其女性患者使用激素的个人安全性。