Population genomic variation, functional biology, and the risk of venous thrombosis

群体基因组变异、功能生物学和静脉血栓形成的风险

• 批准号: 9750789
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 71.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-19 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750789
• 关键词: Aging; Animal Model; Biological; Biological Assay; Biological Process; Biological Testing; Biology; Blood Coagulation Factor VII; Candidate Disease Gene; Cardiovascular Diseases; Cell model; Clinical; Endothelium; Epidemiologist; Fibrin; Fibrin fragment D; Fibrinogen; Gene Structure; Genes; Genetic; Genetic Variation; Genomics; Goals; Health; Hemostatic Agents; Hemostatic function; Human; In Vitro; Individual; International; Investigation; Laboratories; Link; Measures; Modeling; Molecular; Molecular Genetics; National Heart, Lung, and Blood Institute; Pathway interactions; Phenotype; Physicians; Physiological; Plasma; Plasminogen Activator Inhibitor 1; Population; Population Genetics; Productivity; Protein C; Proteins; Regulation; Regulator Genes; Research; Resources; Risk; Scientist; Small Interfering RNA; Structural Genes; Testing; Thromboembolism; Thrombosis; Time; Translating; Validation; Variant; Venous; Venous Thrombosis; Work; analytical tool; base; bioinformatics resource; clinical phenotype; cohort; follow-up; gene product; genetic architecture; genetic information; genetic variant; genomic epidemiology; genomic variation; improved; in vivo; in vivo Model; insight; interest; mouse model; novel; novel strategies; precision medicine; preservation; release factor; screening; von Willebrand Factor; whole genome; working group

Abstract The promises of precision medicine leading to healthier lives, free of the burden of cardiovascular diseases, will be hastened by creating timely, efficient, and effective scientific conduits that rapidly move newly characterized molecular genetic information between genetic epidemiologists and functional biologists. Within the setting of 2 international consortia on the genetics of hemostasis phenotypes and venous thromboembolism (VTE), a network of genetic epidemiologists have successfully collaborated to identify and to replicate novel associations of loci with VTE and thrombosis-related phenotypes, a few of which have undergone functional testing. The goals of this project are 2-fold: (a) to coordinate and advance new genetic discovery in the setting of the 2 international consortia on hemostasis phenotypes (Cohorts for Health and Aging Research in Genomic Epidemiology [CHARGE] Consortium) and VTE (International Network of Venous Thrombosis [INVENT] Consortium); and (b) to follow-up the discoveries with functional biology work conducted by laboratory-based research using cell and animal models that will provide new biologic insights. The CHARGE Hemostasis Working Group coordinates genomic discovery in key hemostasis-related phenotypes from 42 studies and the INVENT consortium coordinates genomic discovery in the VTE phenotype from 12 studies. The genetic discoveries made thus far have provided new biologic insights to the regulation of key hemostasis proteins and VTE risk in genes not previously known to be involved biologically, such as STXBP5 and TC2N, associated with von Willebrand factor and VTE, and TSPAN15 and SLC44A2, associated with VTE. A growing limitation to our scientific productivity has been the challenge of replication: as more studies join consortia for discovery, fewer studies are available for replication. An alternative approach, which accelerates scientific discovery, is to move discoveries that have been prioritized by bioinformatics resources directly to functional testing in the laboratory. Another challenge to new discovery has been the lack of analytic tools that are practical in the consortia setting to analyze across phenotypes in discovery efforts. Recently, however, new approaches that use genetic correlations to facilitate multi-phenotype investigations have emerged and can now be applied using hemostasis phenotypes. In this application, we apply these new approaches to advance genetic and functional discovery and validation efforts via 3 aims. Each aim contains novel work to be accomplished in the proposed 4-year project leverages existing and soon-to-be released genomic resources to achieve the overall goal of characterizing functional physiologic diversity that leads to clinical thrombosis in humans.

摘要 精准医学带来了更健康的生活，摆脱了心血管疾病的负担， 将通过创建及时、高效和有效的科学渠道快速移动到新的 描述了遗传流行病学家和功能生物学家之间的分子遗传信息。在 止血表型和静脉遗传的2个国际联合体的建立 血栓栓塞症(VTE)，一个遗传流行病学家的网络，已经成功地合作识别和 复制与VTE和血栓相关表型相关的基因座的新关联，其中一些具有 经过了功能测试。该项目的目标有两个：(A)协调和推进新的遗传 在2个止血表型国际联合体(健康和健康队列)的背景下的发现 基因组流行病学中的老龄化研究[CHAGE]联合会)和VTE(国际静脉网络 血栓形成[发明]联合体)；和(B)通过开展功能生物学工作来跟踪这些发现 通过使用细胞和动物模型进行的基于实验室的研究，这将提供新的生物学见解。这个 电荷止血工作组协调关键止血相关表型的基因组发现 来自42项研究，发明财团协调了12项VTE表型的基因组发现 学习。到目前为止所取得的基因发现为关键基因的调控提供了新的生物学见解。 STXBP5等以前未知的生物学相关基因中的止血蛋白和VTE风险 TSPAN15和SLC44A2与von Willebrand因子和VTE相关 VTE。随着更多的研究，我们科学生产力的一个日益增长的限制是复制的挑战： 加入发现联盟，可供复制的研究就更少了。另一种方法，即 加速科学发现，就是推动生物信息学资源优先考虑的发现 直接在实验室进行功能测试。新发现的另一个挑战是缺乏分析 在联盟环境中实用的工具，用于在发现工作中跨表型进行分析。最近， 然而，利用遗传相关性促进多表型研究的新方法已经 出现了，现在可以用止血表型来应用。在本应用程序中，我们应用了这些新功能 通过3个目标推进基因和功能发现和验证工作的方法。每个目标都包含 在拟议的四年项目中要完成的新工作利用了现有的和即将发布的工作 基因组资源以实现表征功能生理多样性的总体目标，从而导致 人类的临床血栓形成。