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.