We are using functional genomics approaches to characterize and functionally annotate risk variants for cardiovascular diseases (CVD) (Findley et al, 2018 Biorxiv). We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium, a common site of pathology in cardiovascular disease. We confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli; computationally annotated candidate regulatory variants for the transcriptional response; and identified latent environmental contexts in the GTEx and the Cardiogram datasets. Interestingly, our study showed that each treatment may amplify or buffer genetic risk for coronary artery disease, depending on the particular risk variant considered. We are now using this approach to investigate the role of GxE in cardiovascular disease using IPSC-derived cardiomyocytes and a large panel of vascular endothelial cells from African American healthy donors.