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

• 批准号: 8529609
• 负责人: David Ginsburg
• 金额: $ 37.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8529609
• 关键词: ABO blood group system; Accounting; Address; Affect; Alleles; Antithrombin III; Architecture; Biology; Blood Clot; 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; risk variant; structural genomics; tool; trait; von Willebrand Factor

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）：深静脉血栓形成（DVT）和肺栓塞（PE），统称为静脉血栓栓塞（VTE），是美国第三大最常见的血管性死亡原因，仅次于心脏病发作和中风。目前的数据表明，遗传因素导致> 60%的VTE风险。然而，在最近的全基因组关联研究（GWAS）中证实的已知常见变异，如因子V莱顿和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个人的外显子组测序与无端静脉血栓栓塞。通过集中研究与已知凝血、纤溶和VTE基因网络相对应的27个基因，我们在8个位点鉴定出13个杂合突变。此外，我们通过对基因和血液凝固研究（金斯伯格、德施、密歇根大学）和Trinity学生研究（Brody、Malloy、NHGRI和爱尔兰Trinity学院）的579个兄弟姐妹中的3384名个体进行基因分型和测量VWF水平，研究了血浆血管性血友病因子（VWF）的遗传决定因素，VWF是一种对血栓形成风险具有既定影响的血浆蛋白。Trinity学生研究（Brody、Malloy、NHGRI和Trinity College，爱尔兰）。我们的VWF抗原水平的GWAS证实ABO和VWF是调节血浆VWF的主要共同位点，通过连锁分析鉴定了GWAS未检测到的另外4个新位点。本提案的目的1将该队列的研究扩展至血栓形成风险的其他潜在修饰物，如FV、FVIII、纤溶酶原、派-1、D-二聚体、抗凝血酶III、蛋白S和蛋白C。目的II和III侧重于分析VTE患者队列，以充分说明影响VTE风险的罕见变异的潜在贡献。我们建议对250例无端VTE患者进行全外显子组测序，并将鉴定的突变模式与对照组进行比较。将在更大的复制队列中通过靶向重测序和/或基因分型来分析具有罕见变异的显著聚类的基因座。将从与GIFT研究（Visser和Reitsma，Leiden University，NL）以及ELATE和DODS队列（Kearon，McMaster，Canada）合作的已建立队列中抽取用于分析的DNA样本。我们组建了一支经验丰富的综合研究团队，来自实验基因组学、统计遗传学、凝血和血栓形成生物学、医学遗传学和临床护理等多个学科。这些结果将大大促进我们对VTE发病机制的遗传基础的理解，并提高我们识别VTE高危患者的能力。