VENOUS THROMBOEMBOLISM: GENES, RISK, MANAGEMENT

静脉血栓栓塞：基因、风险、管理

• 批准号: 6505092
• 负责人: EDWIN Gladstone BOVILL
• 金额: $ 18.67万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6505092
• 关键词: Canada; France; Native Americans; blood coagulation disorders; clinical research; congenital blood protein disorder; disease /disorder proneness /risk; family genetics; fibrinolysis; gene environment interaction; gene mutation; genetic susceptibility; hemostasis; human genetic material tag; human subject; linkage mapping; polymerase chain reaction; protein C; thromboembolism; thrombosis; vitamin K

We propose to investigate gene-gene and gene-environmental interactions in venous thrombosis with the goal of better defining individualized clinical risk profiles, optimal, optimal clinical management practices and underlying pathophysiology. Our study population is a group of extended, related thrombophilic pedigrees of French/French Canadian descent (n=1400), living in France, Quebec and Vermont, which share type I protein C deficiency due to a rare 3363 C insertion mutation. The mutation exhibits haplotypic identity across the Quebec, Vermont and probably French families. Thus, the abnormal allele is identical across the population with respect to not only protein C coding and intronic sequence but also related nearby regulatory or co-regulated elements. Therefore, our study population creates a unique opportunity to study the multicausal nature of thrombosis with one of the major modifying loci held constant. Some of these families have been studied by investigators for up to 15 years. We will study the following hypotheses in this study population by a combination of an ambispective longitudinal familial cohort study and molecular biologic strategies focused on gene discovery: 1. The risk for venous thrombosis is a function of a definable subset of oligogenic and environmental factors and their interaction. 2. Clinical management will be improved by better understanding of individual global risk profiles. 3. Quality of life will be affected to varying degrees by the knowledge of an individual's risk profile as well as the presence of disease. 4. Expression of many individual and composite biochemical risk factors, characterized as continuous variables, will reflect the inheritance of single genes that can be localized within the genome. This collaborative clinical study will bring together complementary expertise from five major academic centers, with existing collaborative relationships, in North America and Europe.

我们建议研究静脉血栓形成中的基因-基因和基因-环境相互作用，目的是更好地定义个性化的临床风险特征，最佳的临床管理实践和潜在的病理生理学。我们的研究人群是一组扩展的、相关的法国/法裔加拿大人的血栓形成家系（n=1400），居住在法国、魁北克和佛蒙特州，由于罕见的3363 C插入突变，这些人共有I型蛋白C缺乏症。该突变在魁北克、佛蒙特和可能的法国家族中表现出单倍型同一性。因此，异常等位基因在整个群体中不仅在蛋白C编码和内含子序列方面是相同的，而且在相关的附近调节或共调节元件方面也是相同的。因此，我们的研究人群创造了一个独特的机会来研究血栓形成的多原因性质，其中一个主要的修饰位点保持不变。其中一些家庭已经被调查人员研究了长达15年。本研究将结合前瞻性纵向家族队列研究和以基因发现为重点的分子生物学策略，在本研究人群中研究以下假设：1。静脉血栓形成的风险是一个功能的寡基因和环境因素及其相互作用的一个可定义的子集。2.通过更好地了解个体总体风险状况，将改善临床管理。3.生活质量将在不同程度上受到个人风险状况以及疾病存在的影响。4.许多个体和复合生化危险因素的表达，其特征在于连续变量，将反映可定位于基因组内的单个基因的遗传。这项合作临床研究将汇集来自北美和欧洲五个主要学术中心的互补专业知识，并与现有的合作关系。