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: 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
• 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

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），共同称为静脉血栓栓塞（VTE），是美国血管死亡的第三大最常见原因，仅次于心脏病发作和笔触。当前数据表明遗传因素占VTE风险的60％。然而，在最近的全基因组关联研究（GWAS）（例如因子V Leiden和ABO血液组）中证实的已知常见变体仅占这种风险的一半。 VTE的其余遗传决定因素尚未确定，但可能涉及共同多态性，稀有突变和结构性基因组变异的组合。在初步研究中，我们完成了8个无端VTE的个体的外显子组测序。通过重点关注与已知凝血，纤维蛋白水解和VTE基因网络相对应的27个基因，我们在8个基因座上鉴定了13个杂合突变。 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爱尔兰三一学院）。我们的VWF抗原水平的GWAS证实ABO和VWF是调节等离子体VWF的主要基因座，并通过GWAS未发现的链接分析确定了4个其他新型基因座。该提案的目标1将将该队列的研究扩展到其他潜在的血栓形成风险的修饰符，例如FV，FVIII，纤溶酶原，PAI-1，D-二聚体，抗凝血酶III，蛋白C和Protin C. AIM C. II II和III，专注于对VTE患者进行分析，以解决稀有差异的危险贡献，以解决VETE患者的群体分析。我们建议在250例无端VTE患者的发现组中进行整个外显子组测序，并将鉴定的突变模式与对照中的突变模式进行比较。具有罕见变化的显着聚类的基因座将通过在较大的复制队列中进行重新取代和/或基因分型来分析。用于分析的DNA样本将与既定的同伙一起与礼品研究（Visser and Reitsma，NL Leiden University，NL）以及Elate和Dods Cohorts（Kearon，Kearon，McMaster，加拿大）合作。我们组建了一个经验丰富的研究人员团队，来自几个学科，例如实验基因组学，统计遗传学，凝结和血栓形成生物学，医学遗传学和临床护理。结果应显着提高我们对VTE发病机理遗传基础的理解，并增强我们确定VTE高风险患者的能力。