Thrombosis genetics in African Americans

非裔美国人的血栓形成遗传学

• 批准号: 9912811
• 负责人: Leslie A Lange
• 金额: $ 74.42万
• 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: 2017-04-20 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912811
• 关键词: African American; American; Anticoagulants; Atherosclerosis; Bioinformatics; Biological; Biological Markers; Biology; Blood; Blood Vessels; Blood coagulation; CD14 gene; Cardiovascular Diseases; Cause of Death; Clinical; Coagulation Process; Code; Complement Factor D; Complex; Data; Data Set; Disease; Disease Outcome; Environmental Risk Factor; Ethnic Origin; Ethnic group; European; Event; Factor VIII; Factor VIIa; Factor XII; Factor XIa; Fibrin fragment D; Fibrinogen; Fibrinolytic Agents; Generations; Genetic; Genetic study; Genomics; Health; Hemorrhage; Hemostatic function; Heritability; Inflammation; Inflammatory; Interleukin 2 Receptor; Ischemic Stroke; Jackson Heart Study; Knowledge; Laboratories; Measurement; Measures; Mediation; Minority; Modality; Multi-Ethnic Study of Atherosclerosis; Myocardial Infarction; National Heart, Lung, and Blood Institute; Participant; Pathway interactions; Phenotype; Plasma; Population; Population Genetics; Predisposition; Race; Reasons for Geographic And Racial Differences in Stroke; Risk; Risk Factors; Role; Safety; Sample Size; Sampling; Signal Transduction; Stroke; System; Therapeutic; Thrombin; Thromboplastin; Thrombosis; Thrombus; Trans-Omics for Precision Medicine; United States; Untranslated RNA; Validation; Variant; Venous; Venous Thrombosis; atherosclerotic plaque rupture; base; cardiovascular disorder risk; cardiovascular health; carotid intima-media thickness; cohort; coronary artery calcification; database of Genotypes and Phenotypes; epidemiology study; ethnic disparity; gamma Fibrinogen; genetic approach; genetic association; genetic variant; genome wide association study; genome-wide; genomic locus; health disparity; in vivo; innovation; interest; novel; novel marker; novel strategies; racial disparity; rare variant; risk variant; thrombogenesis; vascular inflammation; whole genome

ABSTRACT Cardiovascular diseases are the leading cause of death in the United States, and disproportionate rates are seen in minority African American populations. Thrombosis and vascular inflammation are important contributors to atherosclerotic plaque rupture and vascular occlusion that underlie myocardial infarction, ischemic stroke, as well as venous thromboembolic disease. The identification of novel biomarkers and their assessment in different ethnic populations can augment the information obtained from traditional CVD risk factors as well as illuminate underlying disease mechanisms and health disparities. While blood biomarkers have been shown to be critically important in the study of CVD, there is a deficit of studies of these measures in African American populations. Preliminary data suggest that thrombin generation, as quantified ex vivo by plasma measurement of endogenous thrombin potential (ETP) is a novel approach to understanding the connection of both the intrinsic and extrinsic coagulation pathways to thrombus formation in vivo. Whole genome sequence (WGS) data, including both coding and functional noncoding variants, are required to identify the full spectrum of contributions of rare variants to common diseases. WGS data are particularly important among non-European ancestry groups, where there is still relatively limited genomic information. Using stored baseline Jackson Heart Study (JHS) plasma samples from 3,500 African Americans, we propose to measure several emerging thrombosis and inflammation plasma biomarkers (endogenous thrombin potential, fibrinogen gamma', coagulation factors VIII and VIIa, soluble interleukin-2 receptor, soluble CD14, and soluble CD163) that are likely to reflect and/or account for increased thrombogenicity and therefore may contribute to higher rates of CVD in African Americans. We will assess the association of thrombosis biomarkers and biomarker-associated genetic variants with more complex subclinical and clinical CVD endpoints available in JHS and other African American cohorts, including REGARDS. By adding these key measures of thrombosis and inflammation to the JHS and REGARDS data sets, utilizing existing whole genome sequence data available through the NHLBI TOPMed project, and using innovative analytical and population genetic approaches, we will be able to greatly expand our knowledge of the role of thrombosis and inflammation in CVD health disparities.

摘要 心血管疾病是美国的主要死亡原因， 在少数非裔美国人中，这一比例不成比例。血栓形成和 血管炎症是动脉粥样硬化斑块破裂和血管病变的重要因素 心肌梗死、缺血性卒中和静脉血栓的基础闭塞 血栓栓塞性疾病。新的生物标志物的鉴定及其在中国的评价 不同种族的人群可以增加从传统心血管疾病风险中获得的信息 这些因素并阐明了潜在的疾病机制和健康差距。当鲜血 生物标记物已被证明在心血管疾病的研究中至关重要，但缺乏 在非裔美国人群体中对这些措施的研究。初步数据显示， 凝血酶生成，如通过血浆内源性凝血酶测定来量化体外 势(ETP)是一种新的方法来理解内在的和 体内血栓形成的外源性凝血途径。全基因组序列(WGS) 需要数据，包括编码和功能非编码变体，以识别完整的 罕见变异对常见疾病的贡献谱。WGS数据尤其是 在非欧洲血统群体中很重要，那里的基因组仍然相对有限 信息。使用存储的3500名杰克逊心脏研究(JHS)的基线血浆样本 非裔美国人，我们建议测量几个新出现的血栓和炎症 血浆生物标志物(内源性凝血酶潜力、纤维蛋白原、凝血因子VIII 和VIIa、可溶性白介素2受体、可溶性CD14和可溶性CD163)可能 反映和/或解释血栓形成能力的增强，因此可能导致更高的 非裔美国人的心血管疾病发生率。我们将评估血栓形成生物标记物的相关性 以及具有更复杂的亚临床和临床脑血管病的生物标记物相关遗传变异 JHS和其他非裔美国人队列中提供的端点，包括问候。通过添加 JHS的血栓形成和炎症的这些关键指标，并考虑到数据集， 利用通过NHLBI TOPMed项目获得的现有全基因组序列数据， 使用创新的分析和种群遗传学方法，我们将能够极大地 扩大我们对血栓形成和炎症在心血管疾病健康差异中的作用的知识。