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: 10579291
• 负责人: NICHOLAS L SMITH
• 金额: $ 63.68万
• 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/10579291
• 关键词: Anticoagulants; Biological; Biological Assay; Biological Process; Biology; Blood flow; Candidate Disease Gene; Circulation; 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; 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.

摘要 静脉血栓栓塞（VTE）是一种临床病症，其包括深静脉血栓形成（DVT）， 腿部和骨盆的深静脉，以及肺栓塞（PE），肺动脉中的凝块。肺 栓子主要是从深静脉移动到肺部的移位的DVT凝块的结果， 阻碍血液流动，往往是致命的这项建议的目的是确定遗传变异 与DVT患者的肺静脉凝块栓塞相关，并表征其生物学特征， 这一过程背后的病理学。对栓塞相关因素知之甚少，包括遗传因素。 知识差距大，知识差距大。唯一确定的栓塞遗传预测因子是rs6025。 凝血因子V（FV）结构基因（F5）中的变体; rs6025已反复显示为凝血因子V（FV）结构基因（F5）中的一种变体。 与DVT伴PE（OR ~2.1）相比，DVT不伴PE（OR ~4.8）的预测因子更强。我们知道 关于F5变异体rs6025对FV蛋白功能的功能性后果， 不能解释差异性DVT-PE效应。我们有初步数据表明另一个非- 同义F5变体rs 4524-与rs6025不连锁不平衡-也与 DVT-PE风险此外，在其他良好的条件下未观察到F5变体的DVT-PE风险的这种差异。 已确定的VTE变体，包括F2（凝血酶原）和ABO。没有大规模的基因发现工作 已经进行了鉴定与DVT-PE风险差异相关的新基因座，也没有系统的 对已知基因座的研究一直在进行，以表征潜在的生物学特性。本提案的目的是 填补这些科学空白。研究机构是国际静脉血栓防治网络 （INVENT）Consortium从15项全基因组研究中收集了超过35，000例VTE病例， 位于查佩尔山的北卡罗来纳州大学的沃尔伯格实验室，专门研究 凝块形成、结构和稳定性的机制。有三个目标。目的1：VTE亚表型：使用 现有关于VTE分类的研究资料，我们将对35,049例VTE病例进行亚表型识别 仅患有DVT的患者和患有PE的患者，无论是否诊断为DVT。目标2：基因发现：我们将 然后进行全基因组关联研究荟萃分析，估计PE的风险， 深静脉血栓将进行不可知和候选变体测试。将在12，000多个 VTE病例。目的3：功能生物学：我们将进行基因及其变体的功能性询问， 已知与DVT-PE风险差异相关。我们的方法是提供生物学证据 从系统的、还原的、以功能为中心的实验中。初期工作将集中在F5 rs6025和rs 4524上; 随后的工作将询问其他新的协会在功能测定凝块形成，结构， 稳定这项工作将推进我们对肺静脉血栓栓塞的生物学理解， 提供机会，以减少归因于PE的死亡。