Identifying novel genetic risk factors for venous thromboembolism (VTE)

描述(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症(VTE)，是美国血管死亡的第三大常见原因，仅次于心脏病发作和中风。目前的数据表明，遗传因素导致了60%的静脉血栓栓塞症风险。然而，已知的常见变异，如因子V莱顿和ABO血型，在最近的全基因组关联研究中得到证实，只占这种风险的一半。VTE的其余遗传决定因素尚未确定，但可能涉及常见的多态、罕见的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例无缘性静脉血栓栓塞者的外显子组测序。通过对27个与已知的凝血、纤溶和血管紧张素转换酶基因网络相对应的基因的研究，我们鉴定了8个基因座的13个杂合子突变。此外，我们通过基因和凝血研究(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)的579个兄弟姐妹的3384人的VWF水平的基因分型和测量，研究了血浆von Willebrand因子(VWF)的遗传决定因素，VWF是一种已被证实对血栓形成风险有影响的血浆蛋白。我们对VWF抗原水平的分析证实了ABO和VWF是调节血浆VWF的主要共同基因座，另外还有4个新的基因座通过连锁分析发现，这些基因座是GWF没有检测到的。这项建议的目的1将把这一队列的研究扩展到其他潜在的血栓形成风险的修饰物，如FV、FVIII、纤溶酶原、PAI-1、D-二聚体、抗凝血酶III、S蛋白和C蛋白。目的II和III侧重于对VTE患者队列的分析，以便充分考虑影响VTE风险的罕见变异的潜在贡献。我们建议对250名无缘无故VTE患者的发现组进行完整的外显子组测序，并将已识别的突变模式与对照组的突变模式进行比较。在一个较大的复制队列中，将通过有针对性的重新测序和/或基因分型来分析具有显著稀有变量聚集性的基因座。用于分析的DNA样本将从与GIFT研究(莱顿大学的Visser和Reitsma)以及Elate和Dods的队列(Kearon，麦克马斯特，加拿大)合作的已建立的队列中提取。我们组建了一支经验丰富的综合研究团队，他们来自几个学科，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。这一结果将大大促进我们对VTE发病机制的遗传学基础的理解，并增强我们识别VTE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.