Functional genomics of GxE in cardiovascular disease: BPA, phthalates and their interactions with gene regulation

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Abstract Cardiovascular disease is the leading global cause of death, accounting for more than 17.9 million deaths per year in 2015, a number that is expected to grow to more than 23.6 million by 2030. Several genetic and environmental factors contribute to cardiovascular disease risk. Bisphenol A and phthalates are two endocrine disruptors that are widely present in plastic and cosmetic products of daily use. These chemicals induce endothe- lial cell death and have been associated with increased risk for atherosclerosis and coronary artery disease. We propose to identify genetic variants that interact with BPA and phthalates and modify gene regulation in vascular cells, with consequences for cardiovascular health. We will use RNA-seq and ATAC-seq to characterize gene expression and chromatin accessibility changes induced by BPA and phthalates in vascular cells. We will focus on vascular endothelial and smooth muscle cells from African American donors, a population group at a higher risk of dying of preventable cardiovascular disease, compared to European Americans, but underrepresented in genetics and functional genomic studies. Using molecular QTL mapping approaches we will discover new gene- environment interactions for BPA and phthalates. We will then use computational predictions and statistical genetics approaches to fine-map these gene-environment interaction signals and colocalize them with associ- ation data for cardiovascular disease. Finally, we propose to use massively parallel reporter assays to validate these GxE in gene expression and deliver a catalog of functionally validated GxE risk factors for cardiovascular disease.