VWF Activity: Molecular Biology, Ethnic Diversity and Disease Associations

VWF 活动：分子生物学、种族多样性和疾病关联

• 批准号: 8965442
• 负责人: Jing-Fei Dong
• 金额: $ 73.05万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965442
• 关键词: ADAMTS; Acute-Phase Proteins; Adhesions; Adhesiveness; Adhesives; Affect; African American; Age Factors; Aging; American; Antigens; Atherosclerosis; Binding; Biological; Biology; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Coagulation Process; Collagen; Communities; Cross-Sectional Studies; Data; Databases; Development; Disease; Endothelial Cells; Environmental Risk Factor; Ethnic Origin; Ethnic group; European; Factor VIII; Factor VIII-Related Antigen; Future; Gene Frequency; Genes; Genetic; Genetic Epistasis; Genetic Variation; Genome; Genotype; Haplotypes; Hemorrhage; Hemostatic function; In Vitro; Incidence; Individual; Injury; Ischemic Stroke; Japanese Population; Laboratories; Measurement; Measures; Mission; Modeling; Modification; Molecular Biology; Myocardial Infarction; Pattern; Peripheral arterial disease; Phenotype; Plasma; Prevalence; Public Health; Research; Risk; Risk Assessment; Sampling; Site; Stroke; Testing; Thrombosis; Thrombus; Time; United States National Institutes of Health; Variant; base; cohort; combat; design; gene environment interaction; genetic variant; genome database; improved; novel; social; trait; von Willebrand Disease; von Willebrand Factor

Project Summary von Willebrand factor (VWF) initiates hemostasis by tethering platelets to sites of vascular injury and participates in the coagulation by protecting the coagulation factor VIII (FVIII) against proteolytic degradation. A low VWF antigen and/or lack of large multimers can result in bleeding, whereas high levels and/or the presence of ultra‐large VWF multimers are associated with thrombosis. This bidirectional activity suggests that VWF expression and adhesive activity are highly regulated to maintain active hemostasis without promoting thrombosis. Plasma VWF levels vary significantly among healthy subjects and there is increasing evidence that this variation is ethnically diverse. Environmental and genetic factors are known to contribute to variations in VWF synthesis, stability, adhesiveness, and clearance, but crucial questions remain. First, what is the relationship between VWF antigen and adhesive activity in healthy individuals? Second, how do genetic variations interact with environmental factors to modify the synthesis and activity of VWF, a known acute phase reactant? Third, how do ethnicity and aging influence the association of variants in the VWF gene with VWF adhesive activity and the development of thrombotic diseases? We hypothesize that 1) variation in the VWF gene influences not only VWF expression, but also adhesive activity; 2) there is a strong gene‐ environment interaction that influences VWF adhesive activity and this interaction is manifested through covariates as ethnicity, age and FVIII; and 3) evaluating VWF adhesive activity can improve risk assessments for thrombotic diseases compared to modeling VWF antigen alone. Our broad, long‐term objective is to understand VWF biological activity and its modification of disease associations by ethnicity, aging and FVIII. There are three specific aims in this proposal. First is to characterize VWF adhesive activity in subjects from the Atherosclerosis Risk in Communities (ARIC) and the Japanese Suita cohorts, whose VWF antigen was consistently measured as low (≤ 50%) or high (≥ 200%) in samples collected over 25 years. VWF adhesive activity and rates of VWF synthesis and clearance will be determined to define 1) an intrinsic relationship between VWF levels and adhesive activity and 2) the impact of aging and ethnicity on this relationship. Second is to 1) identify genetic variants associated with VWF antigen and adhesive activity in subjects from three ethnic groups of European American, African Americans, and Japanese; 2) detect ethnic modifications of these associations; and 3) detect the genetic epistasis and novel molecular interactions that regulate the VWF antigen and adhesive activity. Third is to determine 1) if measuring VWF activity and rates of VWF synthesis‐ clearance improve risk predictions for myocardial infarction, ischemic stroke, and peripheral arterial disease than VWF antigen alone; 2) if subjects with low VWF and/or adhesive activity are protected from these diseases; and 3) how ethnicity and aging modify the risk. The research is highly relevant to the mission of NIH in combating aging‐associated thrombotic and bleeding disorders to improve public health in the US.

项目摘要 冯维勒布兰德因子 (VWF) 通过将血小板束缚在血管损伤部位来启动止血，并通过保护凝血因子 VIII (FVIII) 免遭蛋白水解降解来参与凝血。 低 VWF 抗原和/或缺乏大的多聚体可能导致出血，而高水平和/或存在超大 VWF 多聚体则与血栓形成相关。这种双向活性表明 VWF 表达和粘附活性受到高度调节，以维持主动止血而不促进血栓形成。健康受试者的血浆 VWF 水平存在显着差异，并且越来越多的证据表明这种差异存在种族差异。众所周知，环境和遗传因素会导致 VWF 合成、稳定性、粘附性和清除率的变化，但关键问题仍然存在。首先，VWF抗原与健康个体的粘附活性之间有何关系？其次，遗传变异如何与环境因素相互作用来改变 VWF（一种已知的急性期反应物）的合成和活性？第三，种族和衰老如何影响 VWF 基因变异与 VWF 粘附活性和血栓性疾病发展的关联？我们假设1）VWF基因的变异不仅影响VWF表达，还影响粘附活性； 2）存在强烈的基因-环境相互作用，影响VWF粘附活性，这种相互作用通过种族、年龄和FVIII等协变量表现出来； 3) 与单独模拟 VWF 抗原相比，评估 VWF 粘附活性可以改善血栓性疾病的风险评估。我们广泛、长期的目标是了解 VWF 的生物活性及其对种族、衰老和 FVIII 疾病关联的改变。 该提案有三个具体目标。首先是对来自社区动脉粥样硬化风险 (ARIC) 和日本吹田队列的受试者的 VWF 粘附活性进行表征，在 25 年收集的样本中，其 VWF 抗原始终测量为低 (≤ 50%) 或高 (≥ 200%)。将确定 VWF 粘附活性以及 VWF 合成和清除率，以定义 1) VWF 水平和粘附活性之间的内在关系，以及 2) 衰老和种族对这种关系的影响。 其次是1）在来自欧洲裔美国人、非裔美国人和日本人三个种族群体的受试者中鉴定与VWF抗原和粘附活性相关的遗传变异； 2）检测这些协会的种族变化； 3) 检测调节VWF抗原和粘附活性的遗传上位性和新的分子相互作用。第三是确定 1) 与单独的 VWF 抗原相比，测量 VWF 活性和 VWF 合成清除率是否可以改善心肌梗塞、缺血性中风和外周动脉疾病的风险预测； 2) 具有低VWF和/或粘附活性的受试者是否能够免受这些疾病的影响； 3) 种族和老龄化如何改变风险。这项研究与 NIH 对抗衰老相关血栓和出血性疾病以改善美国公众健康的使命高度相关。