Mayo Clinic Thrombosis and Hemostasis Research Center

梅奥诊所血栓与止血研究中心

• 批准号: 7470681
• 负责人: John A. Heit
• 金额: $ 22万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470681
• 关键词: Mayo; Clinic; Thrombosis; Hemostasis; Research

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.

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。隔离分析表明，VTE是高度遗传的。 VTE及其已知的环境风险因素的高流行率表明，不同作用的多个基因涉及确定VTE易感性。我们假设（1）（1）有一些可发现的基因和基因型大大增加了VTE的风险，（2）某些基因型可能通过VTE风险因素暴露表现出来，并且（3）有定量性状基因座（QTL）会对两种质量型的质量静脉曲张影响两种质量静脉曲张止痛感相关的风险因素和VTE。为了解决这些假设，我们将使用八个血小板中心试点站点和疾病控制中心的资源来识别高风险VTE血统中的易感基因。我们的具体目的是： 目的1。要识别和扩展高风险的VTE血统，收集DNA和血浆的人口统计学和VTE风险因素数据以及样本，以及在这些谱系中为500,000个单核苷酸多态性标记物在整个基因组中均匀间隔的500,000个单核苷酸多态性标记。我们将至少确定适合连锁研究的75个高风险VTE谱系（至少有3个受影响的家庭成员，ELOD分数= 0.3或更高）；基因分型将对约1200个家庭成员进行；目的2。通过遗传链接分析来绘制VTE敏感性基因。我们将使用常规的链接策略，但我们还将实施将环境协变量纳入分析中的最新方法； AIM 3。使用AIM 1，（a）的高风险VTE血统和基因型来确定基因对VTE风险的联合作用和许多定量止血相关的表型； （b）识别包含基因（例如QTL）的区域，这些区域会影响高度可遗留的定量表型的变异，这些定量表型使用方差成分方法方法来与VTE在遗传上与VTE相关，以实现定量性状；目标4。修改蛋黄酱血栓形成注册表以符合血栓形成/止血研究网络注册表，并继续数据抽象，预期结果随访以及梅奥血栓形成中心患者的网络注册表输入。含义：通过这样的努力，网络将促进基于家庭基因发现的研究资源的发展 这将定位为VTE的遗传风险表征并进行未来的翻译研究，包括针对高风险组的干预措施。