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: 9159974
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9159974
• 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 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 Genes; 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; 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.项目总结/摘要 本项目的主要目标是提高对血栓形成的基础和临床知识。凝血酶过量 生成导致血栓形成，包括静脉血栓栓塞（VTE），这是一种复杂的 疾病基于基因组学的研究应该是发现VTE危险因素的有力工具，但GWAS 增加了一些新的见解。与以常见基因变异为中心的GWAS相反，新外显子组 基因分型阵列允许在整个基因组中询问罕见的功能变体。种族特异性因果 高加索人、日本人和中国人人群中VTE的因素涉及凝血蛋白的罕见变异。 VTE风险的遗传性缺失可能部分归因于罕见或低频率变异。外显子组 基因分型可以询问> 250，000个变异，以寻找可能改变蛋白质结构的罕见错义变异。 功能活动。我们首次将外显子组阵列技术应用于一组欧洲裔美国人， 一组非裔美国人得出了令人惊讶的发现，这些发现将被证实并扩展到这一领域。 项目虽然与VTE相关的新遗传变异的鉴定代表了重要的和有价值的遗传变异， 因此，关键是要确定新牵连的生物活性是否以及如何影响新牵连的生物活性。 候选基因的产物可能与血栓形成有关。我们最初的外显子组基因分型涉及某些 结构蛋白基因与静脉血栓栓塞风险有关，包括一些肌球蛋白重链基因。这种令人惊讶 这一发现导致发现某些肌球蛋白具有促凝血活性。我们建议将 肌球蛋白通过与凝血因子相互作用促进凝血酶生成的机制。我们也 我建议澄清组成性血浆蛋白，血清淀粉样蛋白A4，与 凝血因子以促进凝血酶生成。该项目的一个主要目标是发现新的遗传稀有 在未充分研究的非洲裔美国人人群中与VTE相关的变异， 这一因素得到了广泛认可。我们最初的外显子组基因分型数据显着确定了一组VTE- 非裔美国人特有的罕见变异和另一组VTE特有的罕见变异， 白人美国人在这个项目中，我们建议研究来自主要合作中心的七个队列 这些研究将包括大约3,000名白人和2,000名非裔美国人。这些部队将 能够复制我们最初的外显子组基因分型的发现，并将促进进一步的努力， 与VTE相关的外显子组罕见变异的发现。如果成功，该项目的新知识将包括 血栓形成相关的罕见遗传变异的发现和新蛋白质的揭示，可能有助于 血栓风险。关于新基因和以前未被识别的蛋白质的新知识将显著地 扩展了我们关于VTE病理生理学的概念，并将对新的诊断或 治疗应用。