Identifying novel genetic risk factors for venous thromboembolism (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），是美国仅次于心脏病发作和中风的血管性死亡的第三大常见原因。目前的数据表明，遗传因素占静脉血栓栓塞风险的60%。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Factor V Leiden和ABO血型，仅占这种风险的一半。VTE的剩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，我们完成了8例非诱发性静脉血栓栓塞患者的外显子组测序。通过关注27个与已知凝血、纤溶和VTE基因网络相对应的基因，我们在8个位点发现了13个杂合突变。此外，我们通过基因分型和测量来自基因和凝血研究（Ginsburg, Desch, University of Michigan）和三一学生研究（Brody, Malloy， NHGRI和Trinity College， Ireland）的3384名个体和579名兄弟姐妹的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有确定影响的血浆蛋白。我们的VWF抗原水平的GWAS证实了ABO和VWF是调节血浆VWF的主要常见位点，并且通过连锁分析发现了另外4个GWAS未检测到的新位点。本提案的Aim 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。Aim II和III侧重于对静脉血栓栓塞患者队列的分析，以充分解决影响静脉血栓栓塞风险的罕见变异的潜在贡献。我们建议对250例非诱发性静脉血栓栓塞患者进行全外显子组测序，并将已确定的突变模式与对照组进行比较。具有显著罕见变异聚类的位点将在更大的复制队列中通过靶向重测序和/或基因分型进行分析。用于分析的DNA样本将从GIFT研究（Visser和Reitsma，莱顿大学，NL）和ELATE和DODS队列（Kearon，麦克马斯特，加拿大）合作建立的队列中提取。我们已经组建了一支经验丰富的综合研究团队，他们来自多个学科，如实验基因组学、统计遗传学、凝血和血栓生物学、医学遗传学和临床护理。该结果将显著促进我们对静脉血栓栓塞发病机制的遗传基础的理解，并提高我们识别静脉血栓栓塞高危患者的能力。

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.