GWAS of Venous Thrombosis

描述（由申请人提供）：我们的总体长期目标是通过关注增加静脉血栓栓塞风险的遗传和环境因素以及这些因素之间的相互作用，确定常见和复杂（多因素）疾病静脉血栓栓塞（VTE）的病因。静脉血栓栓塞是一种常见疾病，在美国每年有超过90万例病例或复发病例；其中，近三分之一是致命的。为了提高生存率和避免并发症，静脉血栓栓塞必须预防。然而，以前预防静脉血栓栓塞的努力一直受到阻碍，因为大多数已知的静脉血栓栓塞环境（临床）危险因素的个体不会发生静脉血栓栓塞。我们假设，在那些暴露于临床危险因素的人群中，遗传易感性将那些暴露于临床危险因素的人与那些不患静脉血栓栓塞的人区分开来。为了支持这一假设，我们已经表明，由于遗传性，静脉血栓栓塞在家庭中存在分离。静脉血栓栓塞遵循一种复杂的遗传模式，涉及多基因和环境暴露。我们的具体目标是：(1)使用NHGRI基因分型设施指定的1M SNP平台进行全基因组关联（GWA）筛选和分析；(2)检验a)环境暴露是否改变了观察到的基因型与VTE（基因-环境相互作用）之间的关系；b)基因间相互作用是否影响VTE易感性；3)通过通路分析检测与VTE相关的snp是否位于功能连锁基因内或邻近基因。我们目前已经储存了829例VTE病例和478例对照的DNA样本，可与NHGRI共享，到2008年7月1日，我们预计将拥有1300例病例和1300例对照的DNA样本。对于所有病例和对照，使用标准化仪器收集了作为静脉血栓栓塞独立风险因素的环境暴露数据。这些数据通过唯一的患者研究编号标识符存储在SAS数据库中，可以轻松快速地共享。使用最先进的统计遗传方法，我们将识别与VTE相关的遗传变异，包括相互作用。我们将迅速和广泛地提供结果数据供研究使用，并协同工作，在参与的生物储存库之间分享经验和专业知识。我们的研究结果将具有潜在的巨大临床效用，允许医生将暴露于临床危险因素的患者分为高和低静脉血栓栓塞风险，识别未暴露于危险中的患者，并更好地进行针对性预防。

DESCRIPTION (provided by applicant): Our overall long-term goal is to determine the etiology of the common and complex (multifactorial) disease, venous thromboembolism (VTE), by focusing on genetic and environmental factors that increase the risk of VTE, and the interactions among these factors. VTE is a common disease with over 900,000 incident or recurrent events in the U.S. annually; of these, almost one-third are fatal. To improve survival and avoid complications, VTE must be prevented. However, previous efforts to prevent VTE have been stymied because most individuals with known environmental (clinical) risk factors for VTE do not develop VTE. We hypothesize that, among those exposed to a clinical risk factor(s), a genetic predisposition distinguishes those who do from those who do not develop VTE. In support of this hypothesis, we have shown that VTE segregates in families due to heritability. VTE follows a complex mode of inheritance involving polygenes and environmental exposure. Our specific aims are: (1) to perform a genome wide association (GWA) screen and analysis using the 1M SNP platform specified by NHGRI genotyping facilities; (2) to test a)whether environmental exposures modify the observed relationship between genotype and VTE (geneenvironment interaction); and b) whether gene-gene interactions influence susceptibility to VTE; and 3) to test whether SNPs associated with VTE are located within or adjacent to genes that are functionally linked using pathway analysis. We currently have stored DNA samples from 829 VTE cases and 478 controls that are available for sharing with NHGRI, and by July 1, 2008, we project that we will have DNA samples from 1300 cases and 1300 controls. For all cases and controls, data on environmental exposures that are independent risk factors for VTE were collected with a standardized instrument. These data are stored in a SAS database by unique patient study number identifier and can be easily and rapidly shared. Using state of the art statistical genetic methods, we will identify genetic variants associated with VTE, including interactions. We will make the resulting data rapidly and widely available for research use and work collaboratively to share experience and expertise across participating biorepositories. Our results will have potentially great clinical utility by allowing physicians to stratify patients exposed to clinical risk factors into high- and low-VTE risk, identify unexposed patients at risk, and better target prophylaxis.