Human exomics genotyping-driven discovery and characterization of proteins related to clinical thrombosis, blood coagulation and thrombin generation

人类外显子组基因分型驱动的与临床血栓形成、血液凝固和凝血酶生成相关的蛋白质的发现和表征

• 批准号: 9762971
• 负责人: JOHN H GRIFFIN
• 金额: $ 48.13万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762971
• 关键词: African; African American; American; Amyloid; Anticoagulants; Apolipoproteins; Basement membrane; Biological; Blood Coagulation Factor; Blood Proteins; Blood coagulation; Candidate Disease Gene; Cardiac; Caucasians; Chinese People; Clinical; Clinical Research; Coagulation Process; Collagen; Complex; Cox Proportional Hazards Models; Data; Diagnosis; Disease; European; Factor Va; Factor Xa; Frequencies; Functional disorder; Gene Proteins; Generations; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Hemorrhage; Hemostatic function; Heritability; Human; Ions; Japanese Population; Knowledge; Laminin; Leg; Life; Link; Lipoproteins; Lung; Myosin ATPase; Myosin Heavy Chains; Patients; Plasma; Plasma Proteins; Population; Prospective Studies; Protein C; Protein S; Proteins; Race; Recurrence; Relative Risks; Reporting; Research; Retrospective Studies; Risk; Risk Factors; Serum; Serum amyloid A protein; Site; Skeletal Muscle Myosins; Structural Protein; Study of serum; Technology; Thrombin; Thromboembolism; Thrombophilia; Thromboplastin; Thrombosis; Tissues; Translating; Variant; Venous; Venous Thrombosis; atherothrombosis; base; caucasian American; cohort; exome; factor V Leiden; gene product; genetic association; genetic risk factor; genetic variant; genome wide association study; improved; in vivo; insight; novel diagnostics; novel therapeutics; protein structure; rare variant; research study; skeletal; spatiotemporal; tool

7. PROJECT SUMMARY/ABSTRACT Advancing basic and clinical knowledge about thrombosis is the major goal of this Project. Excessive thrombin generation causes thrombosis, including venous thromboembolism (VTE) which is a complex disease. Genomics-based research should be a powerful tool for discovery of VTE risk factors, but GWAS had added few new insights. In contrast to GWAS that is centered on common gene variations, new exome genotyping arrays permit interrogation of rare functional variants throughout the genome. Race-specific causal factors for VTE in Caucasian, Japanese and Chinese populations involve rare variants in coagulation proteins. The missing heritability of VTE risk may be attributed, in part, to rare or low frequency variants. Exome genotyping can interrogate > 250,000 variations for rare missense variants that might alter a protein's functional activity. Our initial application of exome array technology to one cohort of European Americans and one cohort of African Americans yielded surprising findings which will be confirmed and extended by this project. While identification of new genetic variants linked to VTE represents significant and valuable genetic associations, it is critical to determine whether and how the biological activities of the newly implicated candidate gene's product may contribute to thrombosis. Our initial exome genotyping implicated certain structural protein genes as being linked to VTE risk, including some myosin heavy chain genes. This surprising discovery led to the discovery that some myosins have procoagulant activity. We propose to characterize the mechanisms by which myosin promotes thrombin generation by its interactions with clotting factors. We also propose to clarify mechanisms by which the constitutive plasma protein, serum amyloid A 4, interacts with clotting factors to promote thrombin generation. A major goal of this project is to discover new genetic rare variants that are linked to VTE among the understudied African American population for whom no genetic risk factor has yet been widely recognized. Our initial exome genotyping data significantly identified a set of VTE- linked rare variants unique to African Americans and another set of VTE-linked rare variants unique to Caucasian Americans. For this project, we propose to study seven cohorts from key collaborating centers wherein these studies will include circa 3,000 Caucasians and 2,000 African Americans. These cohorts will enable replication of our initial exome genotyping-based discoveries and will facilitate efforts for further discoveries of exomic rare variants linked to VTE. If successful, new knowledge from this project will include discovery of thrombosis-related rare genetic variants and revelation of new proteins that may contribute to thrombosis risks. This new knowledge about new genes and previously unrecognized proteins will significantly extend our concepts about VTE pathophysiology and will have potential implications for new diagnostic or therapeutic applications.

7。项目摘要/摘要 促进有关血栓形成的基本和临床知识是该项目的主要目标。过多的凝血酶 产生引起血栓形成，包括静脉血栓栓塞（VTE），这是一个复杂的 疾病。基于基因组学的研究应该是发现VTE风险因素的强大工具，但GWAS已 添加了很少的新见解。与以常见基因变异为中心的GWA相比 基因分型阵列允许对整个基因组中罕见的功能变体进行询问。种族特异性因果 白种人，日本和中国人群中VTE的因素涉及凝血蛋白中的罕见变异。 VTE风险缺失的遗传力可能部分归因于罕见或低频变体。外显子 基因分型可以质疑> 250,000个变体，以使可能改变蛋白质的稀有错义变体 功能活动。我们最初将外来阵列技术应用于一组欧美人和 一群非洲裔美国人提出了令人惊讶的发现，这将被证实和扩展 项目。而与VTE相关的新遗传变异的识别代表了重要而有价值的遗传 关联，确定新涉及的生物学活动是至关重要的 候选基因的产物可能有助于血栓形成。我们最初的外观基因分型牵涉到一定的 结构蛋白基因与VTE风险有关，包括一些肌球蛋白重链基因。这令人惊讶 发现导致发现一些肌动物具有促凝活性。我们建议表征 肌球蛋白通过与凝血因子的相互作用来促进凝血酶产生的机制。我们也是 建议阐明本构血浆蛋白血清淀粉样蛋白A 4与之相互作用的机制 凝血因子促进凝血酶产生。该项目的主要目标是发现新的遗传稀有 与遗传风险没有遗传风险的研究的非洲裔美国人口中的VTE相关的变体 因素尚未得到广泛认可。我们最初的外部基因分型数据显着识别了一组VTE- 链接的稀有变体是非洲裔美国人独有的，另一组与VTE相关的稀有变体是独特的 高加索美国人。对于这个项目，我们建议从主要协作中心研究七个队列 这些研究将包括约3,000名高加索人和2,000名非裔美国人。这些队列将 能够复制我们最初的基于基因分型的发现，并将促进进一步的努力 与VTE相关的EXOMIC稀有变体的发现。如果成功，该项目的新知识将包括 发现与血栓形成相关的稀有遗传变异和新蛋白的启示可能有助于 血栓形成风险。关于新基因和以前未被认可蛋白质的新知识将大大显着 扩展我们对VTE病理生理学的概念，并将对新的诊断或 治疗应用。