Interindividual differences in pharmacological response contribute significantly to the morbidity and mortality often associated with therapeutic treatments of disease. Genetic variation represents a major source of this variability. Yet despite considerable research effort over the past 20 years to identify genetic and other causes of variable drug response, much remains unknown. We posit that this is the result in part of unrecognized gene-environment-drug (GED) and polygenic-drug (PGD) interactions. While the challenges in conducting research in this area are considerable, we believe that significant inroads to understanding GED and PGD interactions can be made by developing sound mechanistic hypotheses and careful design of basic and translational studies. In this Program Project grant application, we propose three, highly interactive research Projects, and two supporting Cores, that together will develop and apply novel, generalizable approaches to understanding and predicting GED and PGD interactions in the context of preventing thromboembolic events in individuals with cardiovascular disease through the use of anticoagulation and antiplatelet drug therapies. The interaction of environmental exposures and anticoagulation/antiplatelet drugs with the vitamin K-dependent coagulation and platelet activation cascades offers an exceptional opportunity to study GED and PGD effects. Central to this effort will be our continued collaboration with American Indian and Alaska Native (AI/AN) populations of the Northwest and Alaska who have unique and often well-defined dietary and other environmental exposures that preliminary data suggests modify the coagulation pathway and platelet function; enrichment of unique, functionally important genotypes; and reduced genomic heterogeneity overall, compared to the general US population. Moreover, there is a strong moral imperative to conduct health research with AI/AN people, as they are often left out of such investigations and, thus, do not receive the potential benefits that such research can provide. Thus, our overall Program goals are to: 1) to advance our understanding of how genetic and environmental factors affect anti-coagulation and anti-platelet pharmacological responses, and 2) to more broadly improve the national environment for genomic research with AI/AN populations.