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) 是一种临床病症，包括深静脉血栓形成 (DVT)，即静脉血栓 腿部和骨盆的深静脉，以及肺栓塞（PE），即肺动脉中的血栓。 栓子主要是深静脉血栓脱落后从深静脉移动到肺部的结果， 阻碍血液流动；它们往往是致命的。该提案的目的是识别遗传变异。 与 DVT 患者肺部静脉血栓栓塞相关，并描述其生物学特征和 对于这一过程的潜在病理学，人们对与栓塞相关的因素知之甚少，包括遗传因素。 因素，并且知识差距很大，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) 中的变异已多次被证明是 没有 PE 的 DVT（比值比 [OR] ~4.8）比有 PE 的 DVT（OR ~2.1）更强。 关于 F5 变体 rs6025 对 FV 蛋白功能的功能影响有很多，但我们的理解 不能解释 DVT-PE 的差异效应 我们有初步数据表明另一个非- 同义 F5 变体 rs4524（与 rs6025 不存在连锁不平衡）也存在差异相关 此外，F5 变异体的 DVT-PE 风险差异在其他健康人群中并未观察到。 已确定的 VTE 变体，包括 F2（凝血酶原）和 ABO 尚未进行大规模的基因发现工作。 已着手识别与 DVT-PE 风险差异相关的新位点，也没有系统性的研究 该提案的目的是对已知基因座进行研究，以表征其潜在的生物学特征。 解决这些科学差距的研究机构是国际抗静脉血栓形成网络。 (INVENT) 联盟，通过 15 项全基因组研究收集了超过 35,000 个 VTE 病例 标记，以及北卡罗来纳大学教堂山分校的沃尔伯格实验室，该实验室专门研究 凝块形成、结构和稳定性的机制 目标 1：VTE 亚表型：使用。 现有关于 VTE 分类的研究信息，我们将对 35,049 个 VTE 病例进行亚表型识别 单独患有 DVT 的患者和患有 PE 的患者，无论是否诊断出 DVT 目标 2：基因发现：我们会。 然后进行全基因组关联研究荟萃分析，估计患有 PE 的风险 将在超过 12,000 个样本中进行 DVT 不可知和候选变异测试。 目标 3：功能生物学：我们将对基因及其变异进行功能询问。 已知与 DVT-PE 风险存在差异相关，我们的方法是提供生物学证据。 初步工作将集中于 F5 rs6025 和 rs4524； 随后的工作将探讨凝块形成、结构和功能分析中的其他新关联。 这项工作将增进我们对肺部静脉血栓栓塞的生物学理解，并可能提高稳定性。 提供减少PE造成的死亡的机会。