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. 项目概要/摘要 提高有关血栓形成的基础和临床知识是该项目的主要目标。凝血酶过多 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 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 却发现 添加了一些新的见解。与以常见基因变异为中心的 GWAS 相比，新外显子组 基因分型芯片可以检测整个基因组中罕见的功能变异。特定种族的因果关系 白种人、日本人和中国人的 VTE 因素涉及凝血蛋白的罕见变异。 VTE 风险遗传性缺失可能部分归因于罕见或低频变异。外显子组 基因分型可以询问超过 250,000 个变异，以找出可能改变蛋白质的罕见错义变异 功能活动。我们最初将外显子组阵列技术应用于一组欧洲裔美国人和 一组非裔美国人得出了令人惊讶的发现，该发现将得到证实并得到扩展 项目。虽然鉴定出与 VTE 相关的新遗传变异具有重要且有价值的遗传意义。 协会，确定新涉及的生物活动是否以及如何进行至关重要 候选基因的产物可能有助于血栓形成。我们最初的外显子组基因分型表明某些 结构蛋白基因与 VTE 风险相关，包括一些肌球蛋白重链基因。这令人惊讶 这一发现导致人们发现一些肌球蛋白具有促凝血活性。我们建议描述 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 提议阐明组成型血浆蛋白、血清淀粉样蛋白 A 4 与 凝血因子促进凝血酶的产生。该项目的一个主要目标是发现新的稀有基因 在未被充分研究的非裔美国人群体中，与 VTE 相关的变异，对他们来说没有遗传风险 因素尚未得到广泛认可。我们最初的外显子组基因分型数据显着识别了一组 VTE- 与非裔美国人特有的罕见变异相关，以及另一组与 VTE 相关的罕见变异 白人美国人。对于这个项目，我们建议研究来自主要合作中心的七个队列 其中这些研究将包括大约 3,000 名白人和 2,000 名非裔美国人。这些群体将 能够复制我们最初基于外显子组基因分型的发现，并将促进进一步的努力 与 VTE 相关的外显子罕见变异的发现。如果成功，该项目的新知识将包括 发现与血栓形成相关的罕见遗传变异，并揭示可能有助于 血栓形成风险。关于新基因和以前未识别的蛋白质的新知识将显着 扩展我们关于 VTE 病理生理学的概念，并将对新的诊断或治疗产生潜在影响 治疗应用。