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（VTE）的遗传流行病学。分离分析表明，VTE具有高度遗传性。静脉血栓栓塞的高发病率及其已知的环境危险因素表明，多种影响不同的基因参与了静脉血栓栓塞易感性的决定。我们推测：(1)存在可发现的特异性基因和基因型可大大增加静脉血栓栓塞的风险；(2)某些基因型可能通过静脉血栓栓塞危险因素暴露表现出来；(3)存在定量性状位点（QTL）对血浆止血相关危险因素和静脉血栓栓塞均有多效性影响。为了解决这些假设，我们将利用8个血栓病中心试点点和疾病控制中心的资源来确定高危静脉血栓栓塞谱系的易感基因。我们的具体目标是：

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.