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.

项目摘要von Willebrand因子（VWF）通过将血小板绑定到血管损伤部位并通过保护凝结因子VIII（FVIII）来侵害蛋白水解降解，从而引发止血。低VWF抗原和/或缺乏大型多聚体可能导致出血，而高水平和/或超大VWF多聚体的存在与血栓形成有关。这种双向活性表明，VWF表达和粘合剂活性受到高度调节，可在不促进血栓形成的情况下保持活性止血。在健康受试者中，血浆VWF水平差异很大，并且有越来越多的证据表明这种变异在种族上是多种多样的。已知环境和遗传因素有助于VWF合成，稳定性，粘合性和清除率的变化，但仍然存在关键问题。首先，健康个体中的VWF抗原和粘合剂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，以改变已知的急性相反应物VWF的合成和活性？第三，种族和衰老如何影响VWF基因中的变体与VWF粘合剂活性和血栓性疾病的发展？我们假设1）VWF基因的变化不仅会影响VWF表达，还会影响粘合活性。 2）有一个强大的基因环境相互作用会影响VWF粘合剂活性，这种相互作用通过协变量表现为种族，年龄和FVIII； 3）评估VWF粘附活性可以改善与单独建模VWF抗原相比，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生物学活性及其对疾病关联的改变，通过种族，衰老和FVIII。该提案中有三​​个具体的目标。首先是表征社区动脉粥样硬化风险的受试者（ARIC）和日本Suta队列中的VWF粘合剂活性，其VWF抗原始终以25年来收集的样品中的VWF抗原始终测量为低（≤50％）或高（≥200％）。 VWF的粘合剂活性和VWF合成和清除率的速率将确定以定义1）VWF水平与粘合活性之间的内在关系； 2）衰老和种族对这种关系的影响。其次是1）确定来自欧美，非裔美国人和日本三个族裔的受试者中与VWF抗原和粘合剂活动相关的遗传变异； 2）检测这些关联的种族修改； 3）检测调节VWF抗原和粘合剂活性的遗传上毒和新型分子相互作用。第三是确定1）与单独使用VWF抗原相比，是否测量了心肌违规，缺血性中风和周围动脉疾病的VWF合成 - 确定性改善风险预测的速率； 2）如果对低VWF和/或粘合剂活性的受试者免受这些疾病的侵害； 3）种族和衰老如何改变风险。这项研究与NIH的使命高度相关，以梳理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。