VENOUS THROMBOEMBOLISM: GENES, RISK, MANAGEMENT

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，以更好地定义个体化临床风险概况，最佳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/法属加拿大血统的亲血栓谱系（n=1400），生活在法国，魁北克和佛蒙特州，由于罕见的3363 C插入突变而共享I型蛋白C缺乏症。这种突变在魁北克、佛蒙特可能还有法国家庭中表现出单倍型的同一性。因此，在整个群体中，异常等位基因不仅在蛋白C编码和内含子序列方面是相同的，而且在附近的相关调控元件或共调控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因果性，其中一个主要的修饰位点保持不变。调查人员对其中一些家庭进行了长达15年的研究。我们将通过双视角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相结合，在本研究人群中研究以下假设：静脉血栓形成的风险是一个可定义的功能子集的少源性和环境因素及其相互作用。2. 通过更好地了解个人全球风险概况，将改进临床管理。3. 生活质量将在不同程度上受到个人风险概况的了解以及疾病的存在的影响。4. 许多个体和复合生化危险因素的表达，具有连续变量的特征，将反映单个基因的遗传，可以定位在基因组内。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，以及现有的合作关系。

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.