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

基本信息

  • 批准号:
    10579291
  • 负责人:
  • 金额:
    $ 63.68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 静脉血栓栓塞症(VTE)是一种临床情况,包括深静脉血栓形成(DVT),血栓形成在 腿部和骨盆的深静脉,以及肺栓塞(PE),这是一种肺动脉血栓。肺 血栓主要是DVT血栓移位的结果,血栓从深静脉进入肺部, 阻碍血液流动;它们往往是致命的。这项提议的目的是识别遗传变异。 与DVT患者肺静脉血栓栓塞术相关,并对其生物学和 这一过程背后的病理基础。对与栓塞术相关的因素知之甚少,包括遗传因素 因素,知识差距很大。唯一已确定的栓塞遗传预测因子是rs6025。 凝血因子V(Fv)结构基因(F5)的变异;rs6025已被反复证明是一种 预测无PE的DVT的优势比(OR)~4.8强于有PE的DVT(OR~2.1)。我们知道一个 关于F5变异体rs6025对Fv蛋白功能的功能影响,但我们的理解是 不能解释不同的DVT-PE效应。我们有初步数据显示,另一个非- 同义的F5变种rs4524--与rs6025没有连锁不平衡--也存在差异关联 有深静脉血栓栓塞症的风险。此外,F5变种的DVT-PE风险的这种差异在其他井型中没有观察到。 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努力 已采取行动确定与DVT-PE风险不同相关的新基因座,也没有系统性的 对已知的基因座进行了调查,以确定潜在的生物学特征。这项提案的目的将是 解决这些科学上的差距。研究环境是国际抗击静脉血栓形成网络 (发明)Consortium,该联盟从15项全基因组研究中积累了超过35,000例VTE病例 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 血栓形成、结构和稳定性的机制。有三个目标。目标1:VTE亚型:使用 根据已有的VTE分类研究资料,我们将对35,049例VTE病例进行亚型鉴定 单纯DVT患者和PE患者,有或没有诊断出DVT。目标2:基因发现:我们将 然后进行一项全基因组关联研究荟萃分析,估计患有AFP的患者发生PE的风险 深静脉血栓形成。将进行不可知和不同候选人的测试。将在超过12,000人中进行复制 VTE病例。目标3:功能生物学:我们将对基因及其变体进行功能询问 已知与DVT-PE风险不同相关。我们的方法将是提供生物证据 来自系统的、还原的、以功能为中心的实验。初步工作将集中在F5 rs6025和rs4524; 随后的工作将在血栓形成、结构和功能分析中询问其他新的关联。 稳定性。这项工作将促进我们对肺静脉血栓栓塞术的生物学理解,并可能 为减少可归因于PE的死亡提供机会。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

NICHOLAS L SMITH其他文献

NICHOLAS L SMITH的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('NICHOLAS L SMITH', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 63.68万
  • 项目类别:
The Association of Vasomotor Symptoms with Thrombosis in Postmenopausal Women
绝经后妇女血管舒缩症状与血栓形成的关系
  • 批准号:
    8747858
  • 财政年份:
    2014
  • 资助金额:
    $ 63.68万
  • 项目类别:
The Association of Vasomotor Symptoms with Thrombosis in Postmenopausal Women
绝经后妇女血管舒缩症状与血栓形成的关系
  • 批准号:
    8890876
  • 财政年份:
    2014
  • 资助金额:
    $ 63.68万
  • 项目类别:
Pharmacologic and pharmacogenetic associations with recurrent venous thrombosis
药理学和药物遗传学与复发性静脉血栓形成的关联
  • 批准号:
    8115913
  • 财政年份:
    2008
  • 资助金额:
    $ 63.68万
  • 项目类别:
Pharmacologic and pharmacogenetic associations with recurrent venous thrombosis
药理学和药物遗传学与复发性静脉血栓形成的关联
  • 批准号:
    8307828
  • 财政年份:
    2008
  • 资助金额:
    $ 63.68万
  • 项目类别:
Pharmacologic and pharmacogenetic associations with recurrent venous thrombosis
药理学和药物遗传学与复发性静脉血栓形成的关联
  • 批准号:
    7895839
  • 财政年份:
    2008
  • 资助金额:
    $ 63.68万
  • 项目类别:
Pharmacologic and pharmacogenetic associations with recurrent venous thrombosis
药理学和药物遗传学与复发性静脉血栓形成的关联
  • 批准号:
    7691281
  • 财政年份:
    2008
  • 资助金额:
    $ 63.68万
  • 项目类别:
Estrogens and pharmacogenetic risks of venous thrombosis in postmenopausal women
绝经后妇女的雌激素和静脉血栓形成的药物遗传学风险
  • 批准号:
    7730104
  • 财政年份:
    2004
  • 资助金额:
    $ 63.68万
  • 项目类别:
Clotting genetic variant, hormones and venous thrombosis
凝血遗传变异、激素和静脉血栓形成
  • 批准号:
    6892153
  • 财政年份:
    2004
  • 资助金额:
    $ 63.68万
  • 项目类别:
Clotting genetic variant, hormones and venous thrombosis
凝血遗传变异、激素和静脉血栓形成
  • 批准号:
    7037591
  • 财政年份:
    2004
  • 资助金额:
    $ 63.68万
  • 项目类别:

相似海外基金

NSF/BIO-DFG: Biological Fe-S intermediates in the synthesis of nitrogenase metalloclusters
NSF/BIO-DFG:固氮酶金属簇合成中的生物 Fe-S 中间体
  • 批准号:
    2335999
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Collaborative Research: Conference: Large Language Models for Biological Discoveries (LLMs4Bio)
合作研究:会议:生物发现的大型语言模型 (LLMs4Bio)
  • 批准号:
    2411529
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Collaborative Research: Conference: Large Language Models for Biological Discoveries (LLMs4Bio)
合作研究:会议:生物发现的大型语言模型 (LLMs4Bio)
  • 批准号:
    2411530
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Collaborative Research: NSF-ANR MCB/PHY: Probing Heterogeneity of Biological Systems by Force Spectroscopy
合作研究:NSF-ANR MCB/PHY:通过力谱探测生物系统的异质性
  • 批准号:
    2412551
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Elucidating mechanisms of biological hydrogen conversion through model metalloenzymes
通过模型金属酶阐明生物氢转化机制
  • 批准号:
    2419343
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Collaborative Research: The Interplay of Water Condensation and Fungal Growth on Biological Surfaces
合作研究:水凝结与生物表面真菌生长的相互作用
  • 批准号:
    2401507
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
DESIGN: Driving Culture Change in a Federation of Biological Societies via Cohort-Based Early-Career Leaders
设计:通过基于队列的早期职业领袖推动生物协会联盟的文化变革
  • 批准号:
    2334679
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
REU Site: Modeling the Dynamics of Biological Systems
REU 网站:生物系统动力学建模
  • 批准号:
    2243955
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Standard Grant
Defining the biological boundaries to sustain extant life on Mars
定义维持火星现存生命的生物边界
  • 批准号:
    DP240102658
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Discovery Projects
Advanced Multiscale Biological Imaging using European Infrastructures
利用欧洲基础设施进行先进的多尺度生物成像
  • 批准号:
    EP/Y036654/1
  • 财政年份:
    2024
  • 资助金额:
    $ 63.68万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了