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: 9313320
• 负责人: Jing-Fei Dong
• 金额: $ 64.42万
• 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/9313320
• 关键词: ADAMTS; Acute-Phase Proteins; Adhesions; Adhesiveness; Adhesives; Affect; African American; Age; Aging; American; Antigens; Atherosclerosis Risk in Communities; Binding; Biological Factors; Biology; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Coagulation Process; Collagen; Cross-Sectional Studies; Data; Databases; Development; Disease; Endothelial Cells; Environmental Risk Factor; Ethnic Origin; Ethnic group; European; F8 gene; 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; ethnic diversity; 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.

血管性血友病因子（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）免受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导致出血，而高水平和/或超大VWF多聚体的存在与血栓形成相关。这种双向活性表明，VWF表达和粘附活性受到高度调节，以保持主动止血而不促进血栓形成。血浆VWF水平在健康受试者中差异显著，越来越多的证据表明这种变化是种族多样性的。已知环境和遗传因素有助于VWF合成、稳定性、稳定性和清除率的变化，但关键问题仍然存在。首先，健康个体中VWF抗原与粘附活性之间的关系是什么？其次，遗传变异如何与环境因素相互作用，以改变VWF（一种已知的急性期反应物）的合成和活性？第三，种族和年龄是如何影响VWF基因变异与VWF粘附活性和血栓性疾病发展的关系的？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）存在影响VWF粘附活性的强基因-环境相互作用，这种相互作用通过协变量如种族、年龄和FVIII表现出来; 3）与单独建模VWF抗原相比，评价VWF粘附活性可以改善血栓性疾病的风险评估。我们广泛的长期目标是了解VWF的生物活性及其对种族，年龄和FVIII疾病相关性的修饰。 这项建议有三个具体目标。首先是表征来自社区动脉粥样硬化风险（ARIC）和日本Suita队列的受试者中的VWF粘附活性，这些受试者的VWF抗原在25年内采集的样本中始终测量为低（≤ 50%）或高（≥ 200%）。将测定VWF粘附活性以及VWF合成和清除速率，以确定1）VWF水平与粘附活性之间的内在关系和2）年龄和种族对该关系的影响。 其次是1）鉴定来自欧洲裔美国人、非洲裔美国人和日本人的三个种族组的受试者中与VWF抗原和粘附活性相关的遗传变异; 2）检测这些关联的种族修饰;和3）检测调节VWF抗原和粘附活性的遗传上位性和新型分子相互作用。第三是确定1）测量VWF活性和VWF合成-清除率是否比单独测量VWF抗原可改善心肌梗死、缺血性卒中和外周动脉疾病的风险预测; 2）VWF和/或粘附活性低的受试者是否可免受这些疾病的影响; 3）种族和年龄如何改变风险。该研究与NIH的使命高度相关，即对抗与衰老相关的血栓形成和出血性疾病，以改善美国的公共卫生。