Identifying novel genetic risk factors for venous thromboembolism (VTE)

识别静脉血栓栓塞 (VTE) 的新遗传风险因素

基本信息

批准号：
8703170
负责人：
David Ginsburg
金额：
$ 38.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703170
关键词：
ABO blood group system Accounting Address Affect Alleles Antithrombin III Architecture Biology Blood Vessels Blood coagulation Body mass index Canada Candidate Disease Gene Cessation of life Coagulation Process Code Cohort Studies Collaborations Complex Complex Genetic Trait DNA Data Deep Vein Thrombosis Development Diagnosis Discipline Disease European Factor V Factor VIII-Related Antigen Factor XI Fibrin fragment D Fibrinogen Future Gene Frequency Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Risk Genetic Techniques Genome Genomics Genotype Height Hemostatic Agents Heritability Host Defense Human Genome Individual Inflammation Ireland Measures Medical Genetics Meta-Analysis Michigan Mutation Myocardial Infarction National Human Genome Research Institute Pathogenesis Pathway interactions Patients Pattern Plasma Plasma Proteins Plasminogen Plasminogen Activator Inhibitor 1 Population Distributions Protein C Protein S Pulmonary Embolism Recording of previous events Research Personnel Risk Sampling Stroke Students System Targeted Resequencing Technology Testing Therapeutic Thromboembolism Thrombosis Universities Variant Venous Work base clinical care cohort college exome sequencing experience factor V Leiden fibrinopeptides gamma genetic linkage analysis genetic risk factor genetic variant genome wide association study high risk innovation lifetime risk novel public health relevance rare variant risk variant structural genomics tool trait von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively referred to as venous thromboembolism (VTE), is the third most common cause of vascular death in the US, after only heart attacks and strokes. Current data suggest that genetic factors contribute to > 60% of VTE risk. However, known common variants, confirmed in recent genome-wide association studies (GWAS), such as Factor V Leiden and the ABO blood group, account for only half of this risk. The remaining genetic determinants for VTE are yet to be determined but may involve a combination of common polymorphisms, rare mutations and structural genomic variants. In preliminary studies, we have completed the exome sequencing of 8 individuals with unprovoked VTE. By focusing on 27 genes corresponding to known coagulation, fibrinolytic, and VTE gene networks, we identified 13 heterozygous mutations at 8 loci. Additionally, we investigated the genetic determinants of plasma von Willebrand Factor (VWF), a plasma protein with an established effect on thrombosis risk, by genotyping and measuring VWF levels in 3384 individuals, in 579 sibships from the Genes and Blood Clotting Study (Ginsburg, Desch, University of Michigan) and the Trinity Student Study (Brody, Malloy, NHGRI and Trinity College, Ireland). Our GWAS of VWF antigen levels confirm ABO and VWF as the major common loci regulating plasma VWF with 4 additional novel loci identified by linkage analysis that were undetected by GWAS. Aim 1 of this proposal will extend the study of this cohort to other potential modifiers of thrombosis risk such as FV, FVIII, plasminogen, PAI-1, D-dimer, antithrombin III, Protein S, and Protein C. Aim II and III focus on analysis of a cohort of VTE patients in order to adequately address the potential contribution of rare variants influencing VTE risk. We propose to perform whole exome sequencing in a discovery group of 250 patients with unprovoked VTE and compare the identified mutation patterns with those in controls. Loci with significant clustering of rare variats will be analyzed by targeted resequencing and/or genotyping in a larger replication cohort. DNA samples for analysis will be drawn from established cohorts in collaboration with the GIFT Study (Visser and Reitsma, Leiden University, NL) and the ELATE and DODS cohorts (Kearon, McMaster, Canada). We have assembled an experienced, integrated team of investigators from several disciplines such as experimental genomics, statistical genetics, coagulation and thrombosis biology, medical genetics and clinical care. The results should significantly advance our understanding of the genetic basis of VTE pathogenesis and enhance our capacity to identify patients at high risk for VTE.

描述（由申请人提供）：深静脉血栓（DVT）和肺栓塞（PE）统称为静脉血栓栓塞（VTE），是美国血管性死亡的第三大常见原因，仅次于心脏病和中风。目前的数据表明，遗传因素导致超过 60% 的 VTE 风险。然而，最近全基因组关联研究 (GWAS) 证实的已知常见变异，例如莱顿因子 V 和 ABO 血型，仅占这种风险的一半。 VTE 的其余遗传决定因素尚未确定，但可能涉及常见多态性、罕见突变和结构基因组变异的组合。在初步研究中，我们已经完成了 8 名无端静脉血栓栓塞患者的外显子组测序。通过关注与已知凝血、纤溶和 VTE 基因网络相对应的 27 个基因，我们在 8 个位点鉴定了 13 个杂合突变。此外，我们通过基因与血液凝固研究（Ginsburg， Desch，密歇根大学）和三一学生研究（Brody、Malloy、NHGRI 和爱尔兰三一学院）。我们的 VWF 抗原水平 GWAS 证实 ABO 和 VWF 是调节血浆 VWF 的主要共同位点，另外还有 4 个通过连锁分析鉴定的新位点，这些位点未被 GWAS 检测到。该提案的目标 1 将该队列的研究扩展到其他潜在的血栓形成风险调节剂，如 FV、FVIII、纤溶酶原、PAI-1、D-二聚体、抗凝血酶 III、蛋白 S 和蛋白 C。目标 II 和 III 重点对一组 VTE 患者进行分析，以充分解决罕见变异影响 VTE 风险的潜在贡献。我们建议对 250 名无端 VTE 患者的发现组进行全外显子组测序，并将识别出的突变模式与对照组的突变模式进行比较。将通过在更大的复制队列中进行靶向重测序和/或基因分型来分析具有显着稀有变异聚类的基因座。用于分析的 DNA 样本将从与 GIFT 研究（荷兰莱顿大学的 Visser 和 Reitsma）以及 ELATE 和 DODS 队列（加拿大麦克马斯特的 Kearon）合作建立的队列中抽取。我们组建了一支经验丰富、综合性的研究团队，其研究人员来自实验基因组学、统计遗传学、凝血和血栓生物学、医学遗传学和临床护理等多个学科。这些结果将显着促进我们对 VTE 发病机制遗传基础的理解，并增强我们识别 VTE 高风险患者的能力。