Mayo Clinic Thrombosis and Hemostasis Research Center

描述（由申请人提供）：我们广泛的长期目标是确定静脉血栓栓塞（VTE）的遗传流行病学。分离分析表明，静脉血栓栓塞是高度遗传。静脉血栓栓塞的高患病率及其已知的环境危险因素表明，多种不同影响的基因参与决定静脉血栓栓塞的易感性。我们假设：（1）存在显著增加VTE风险的特异性可重复基因和基因型，（2）某些基因型可能通过VTE风险因素暴露表现出来，（3）存在多效影响血浆止血相关风险因素和VTE的数量性状位点（QTL）。为了解决这些假设，我们将利用8个血栓形成中心试点和疾病控制中心的资源，以确定高危VTE家系的易感基因。我们的具体目标是： 目标1。为了识别和扩展高风险VTE谱系，收集人口统计学和VTE风险因素数据和DNA和血浆样本，以及这些谱系内的基因型信息个体，用于在整个基因组中均匀分布的500，000个基于单核苷酸多态性的标记。我们将确定至少75个适用于连锁研究的高危VTE家系（至少3个受影响的家族成员，且EHD评分≥ 0.3）;将对约1200个家族成员进行基因分型;目标2。应用遗传连锁分析法定位静脉血栓栓塞症易感基因。我们将使用传统的联系策略，但我们也将实施最新的方法，将环境协变量纳入分析;目标3。使用目标1中的高风险静脉血栓栓塞谱系和基因型，（a）确定基因对静脉血栓栓塞风险和许多定量止血相关表型的联合作用;和（B）识别包含基因的区域（例如，QTL），其影响高度可遗传的数量表型中的变异，所述高度可遗传的数量表型使用数量性状的方差分量方法与VTE遗传相关;以及目的4。修订马约血栓形成登记研究，以符合血栓形成/止血研究网络登记研究，并继续数据提取、前瞻性结局随访和马约血栓形成中心患者的网络登记研究数据录入。意义：通过这些努力，该网络将促进以家庭为基础的基因发现研究资源的发展 这将被定位为描述VTE的遗传风险，并进行未来的转化研究，包括针对高危人群的干预措施。

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.