Genetic Discovery and Functional Validation to Identify Precursors of Clot Embolization in those with a Deep Vein Thrombosis

基因发现和功能验证，以识别深静脉血栓形成患者的血栓栓塞前体

• 批准号: 10414061
• 负责人: NICHOLAS L SMITH
• 金额: $ 64.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414061
• 关键词: Address; Anticoagulants; Biological; Biological Assay; Biological Process; Biology; Blood Circulation; Blood flow; Candidate Disease Gene; Classification; Clinical; Coagulation Process; Cohort Studies; Data; Deep Vein Thrombosis; Diagnosis; Embolism; Event; Factor V; Fibrinolysis; Functional disorder; Genes; Genetic; Genetic Variation; Heart; Hemostatic function; International; Investigation; Knowledge; Laboratories; Lead; Learning; Leg; Life; Link; Linkage Disequilibrium; Lung; Meta-Analysis; North Carolina; Odds Ratio; Other Genetics; Pathology; Pelvis; Phenotype; Process; Proteins; Prothrombin; Pulmonary Embolism; Pulmonary artery structure; Pump; Research; Resistance; Resources; Risk; Risk Estimate; Structural Genes; Structure; Testing; Therapeutic Embolization; Thrombosis; Travel; Universities; Validation; Variant; Venous; Venous Thrombosis; Work; activated Protein C; bioinformatics resource; deep vein; experimental study; genetic information; genetic predictors; genetic risk factor; genetic variant; genome wide association study; genome-wide; genomic locus; insight; interest; mouse model; mutant; novel; protein function; venous thromboembolism

ABSTRACT Venous thromboembolism (VTE) is a clinical condition that includes deep vein thrombosis (DVT), a clot in the deep veins of the legs and pelvis, and pulmonary embolism (PE), a clot in the pulmonary arteries. Pulmonary emboli are primarily a consequence of a dislodged DVT clot that travels from the deep veins to the lungs, obstructing blood flow; they are too often fatal. The aim of this proposal is to identify genetic variation associated with venous clot embolization to the lungs in those with a DVT and to characterize the biology and pathology underlying this process. Little is known about factors associated with embolization, including genetic factors, and the knowledge gap is wide. The only established genetic predictor of embolization is rs6025 variant in the coagulation factor V (FV) structural gene (F5); rs6025 has been shown repeatedly to be a stronger predictor of DVTs without a PE (odds ratios [OR] ~4.8) than of DVTs with a PE (OR ~2.1). We know a lot about the functional consequence of the F5 variant rs6025 on FV protein function, but our understanding does not explain the differential DVT-PE effect. We have preliminary data indicating that another non- synonymous F5 variant, rs4524—not in linkage disequilibrium with rs6025—is also differentially associated with DVT-PE risk. Further, this differential in DVT-PE risk for the F5 variants is not observed for other well- established VTE variants, including F2 (prothrombin) and ABO. No large-scale genetic discovery effort has been undertaken to identify new loci differentially associated with DVT-PE risk, nor has a systematic investigation of known loci been pursued to characterize the underlying biology. The aims of this proposal will address these scientific gaps. The research settings are the International Network Against Venous Thrombosis (INVENT) Consortium, which has amassed over 35,000 VTE cases from 15 studies with genome-wide markers, and the Wolberg Laboratory at the University of North Carolina at Chapel Hill, which specializes in mechanisms of clot formation, structure, and stability. There are 3 aims. Aim 1: VTE Sub-phenotyping: Using existing study information on the classification of VTE, we will sub-phenotype 35,049 VTE cases to identify those with DVT alone and those with PE, with or without a diagnosed DVT. Aim 2: Genetic Discovery: We will then conduct a genome-wide association study meta-analysis that estimates the risk of PE among those with a DVT. Agnostic and candidate-variant testing will be conducted. Replication will be conducted in over 12,000 VTE cases. Aim 3: Functional Biology: We will conduct functional interrogations of genes and their variants that are known to be differentially associated with DVT-PE risk. Our approach will be to provide biologic evidence from systematic and reductive, function-focused experiments. Initial work will focus on F5 rs6025 and rs4524; subsequent work will interrogate other novel associations in functional assays of clot formation, structure, and stability. This work will advance our biologic understanding of venous clot embolization to the lungs and may present opportunities to reduce fatalities attributable to PE.

抽象的 静脉血栓栓塞（VTE）是一种临床状况，包括深静脉血栓形成（DVT），在 腿和骨盆的深静脉，以及肺动脉栓塞（PE），肺动脉中的凝块。 Emboli主要是从深静脉到肺部传播的移位DVT凝块的结果， 阻塞血流；他们经常致命。该建议的目的是确定遗传变异 与具有DVT的患者的肺部栓塞与肺栓塞相关，并表征生物学和 这一过程的基础病理。关于与栓塞相关的因素，包括遗传的因素知之甚少 因素，知识差距很大。栓塞的唯一建立的遗传预测因子是RS6025 凝血因子V（FV）结构基因（F5）中的变体； RS6025反复显示为 与具有PE的DVT相比，没有PE的DVT（或〜2.1）的DVT（赔率比[OR] 〜4.8）更强。我们知道一个 关于F5变体RS6025在FV蛋白函数上的功能后果，但我们的理解 不能解释差异DVT-PE效应。我们有初步数据，表明另一个非 - 同义F5变体，RS4524 - 与RS6025的连锁二驱动器中不相同 有DVT-PE风险。此外，没有观察到其他井的DVT-PE风险差异 已建立的VTE变体，包括F2（凝血酶原）和ABO。没有大规模的遗传发现工作 努力识别与DVT-PE风险不同的新地区，也没有系统 对已知基因座的研究进行了调查，以表征潜在的生物学。该提议的目的将 解决这些科学差距。研究环境是反对静脉血栓形成的国际网络 （发明）财团，从15种基因组研究中积累了35,000多个VTE病例 标记和北卡罗来纳大学教堂山分校的沃尔伯格实验室，该实验室专门从事 凝块形成，结构和稳定性的机制。有3个目标。目标1：VTE子表型：使用 现有的有关VTE分类的研究信息，我们将亚表征35,049 VTE案例识别 单独使用DVT的人和患有PE的人，有或没有诊断性DVT。目标2：遗传发现：我们将 然后进行全基因组关联研究荟萃分析，该研究估计患有PE的风险 DVT。将进行不可知论和候选变异的测试。复制将在12,000多个 VTE案件。目标3：功能生物学：我们将对基因及其变异的功能审查 已知与DVT-PE风险不同。我们的方法是提供生物学证据 从系统和减少，以功能为中心的实验。最初的工作将集中于F5 RS6025和RS4524； 随后的工作将在凝块形成，结构和结构和 稳定。这项工作将使我们对静脉凝结栓塞到肺部的生物学理解，并可能 目前的机会减少了归因于PE的死亡。