Mayo Clinic Thrombosis and Hemostasis Research Center

描述(由申请人提供)：我们广泛的、长期的目标是确定静脉血栓栓塞症(VTE)的遗传流行病学。分离分析表明，VTE具有高度的遗传性。VTE的高患病率及其已知的环境危险因素表明，决定VTE易感性的多个基因具有不同的作用。我们假设(1)存在显著增加VTE风险的特定的可发现基因和基因类型，(2)某些基因可能通过VTE危险因素暴露而显现，(3)存在多向影响血浆止血相关危险因素和VTE的数量性状基因座(QTL)。为了解决这些假设，我们将使用8个血栓形成中心试点站点和疾病控制中心的资源来确定高危VTE家系的易感基因。我们的具体目标是： 目的1.识别和扩展高危VTE家系，收集人口学和VTE危险因素数据以及DNA和血浆样本，以及这些家系中具有基因信息的个体，以获得500,000个均匀分布在基因组中的单核苷酸多态标记。我们将确定至少75个适合进行连锁研究的高危VTE家系(至少3个患病家系成员，Elod评分为0.3或以上)；对~1200个家系成员进行基因分型；目的2.通过遗传连锁分析定位VTE易感基因。我们将使用传统的连锁策略，但我们也将实施在分析中纳入环境协变量的最新方法；目标3.使用目标1的高危VTE家系和基因类型，(A)确定基因对VTE风险和一些与止血相关的定量表型的联合作用；以及(B)使用数量性状的方差分量方法确定包含影响高度可遗传数量表型变异的基因(例如，QTL)的区域；以及目标4.修订梅奥血栓形成/止血研究网络登记表，以符合梅奥血栓形成/止血研究网络登记表，并继续为梅奥血栓形成中心患者进行数据提取、预期结果随访和网络登记数据录入。影响：通过这些努力，该网络将促进开发以家庭为基础的基因发现研究资源 这将定位于确定静脉血栓栓塞症的遗传风险，并进行未来的翻译研究，包括针对高危群体的干预措施。

DESCRIPTION (provided by applicant): Our broad, long-term objective is to determine the genetic epidemiology of venous thromboembolism (VTE). Segregation analyses show that VTE is highly heritable. The high prevalence of VTE and its known environmental risk factors suggest that multiple genes of varying effects are involved in determining VTE susceptibility. We hypothesize that (1) there are specific discoverable genes and genotypes that greatly increase the risk of VTE, (2) some genotypes may manifest through VTE risk factor exposure, and (3) there are quantitative trait loci (QTL) that pleiotropically affect both plasma hemostasis-related risk factors and VTE. To address these hypotheses, we will use the resources of the eight Thrombophilia Center Pilot sites and the Centers for Disease Control to identify susceptibility genes in high-risk VTE pedigrees. Our specific aims are: Aim 1. To identify and extend high-risk VTE pedigrees, collect demographic and VTE risk factor data and samples for DNA and plasma, and genotype informative individuals within these pedigrees for 500,000 single nucleotide polymorphism-based markers evenly spaced throughout the genome. We will identify at least 75 high-risk VTE pedigrees suitable for linkage studies (at least 3 affected family members and ELOD scores=0.3 or higher); genotyping will be done on ~1200 family members; Aim 2. To map VTE susceptibility genes by genetic linkage analysis. We will use conventional linkage strategies, but we will also implement the latest methods that incorporate environmental covariates in the analysis; Aim 3. Using the high-risk VTE pedigrees and genotypes from Aim 1, (a) to determine the joint action of genes on VTE risk and a number of quantitative hemostasis-related phenotypes; and (b) to identify regions containing genes (e.g., QTL) that influence variation in highly-heritable quantitative phenotypes that genetically correlate with VTE using variance components approach for quantitative traits; and Aim 4. To revise the Mayo Thrombophilia Registry to conform to the Thrombosis/Hemostasis Research Network Registry, and continue data abstraction, prospective outcomes follow-up, and Network Registry data entry for Mayo Thrombophilia Center patients. Implications: Through such efforts, the Network will facilitate the development of a family-based gene-discovery research resource that will be positioned to characterize genetic risk of VTE and to conduct future translational studies, including interventions targeted to high risk groups.