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

摘要 心血管疾病是全球主要的死亡原因，造成1790多万人死亡 预计到2030年，这一数字将增长到2360多万。几种遗传和 环境因素会增加心血管疾病的风险。双酚A和邻苯二甲酸酯是两种内分泌物质 广泛存在于日常使用的塑料和化妆品中的干扰物。这些化学物质会诱导内皮细胞- 肝细胞死亡，并与动脉粥样硬化和冠状动脉疾病的风险增加有关。我们 建议识别与双酚A和邻苯二甲酸酯相互作用的遗传变异，并修改血管中的基因调控 细胞，对心血管健康有影响。我们将使用rna-seq和atac-seq来表征基因。 双酚A和邻苯二甲酸酯诱导血管细胞表达和染色质可及性改变。我们将专注于 来自非洲裔美国人捐赠者的血管内皮细胞和平滑肌细胞，这是一个群体 与欧洲美国人相比，死于可预防的心血管疾病的风险，但在 遗传学和功能基因组学研究。利用分子QTL定位方法，我们将发现新的基因-- 双酚A和邻苯二甲酸盐的环境相互作用。然后我们将使用计算预测和统计 fi的遗传学方法定位这些基因-环境相互作用信号，并将它们与相关基因共同定位。 心血管疾病的健康数据。最后，我们建议使用大规模平行报告分析来验证 这些GxE在基因表达中，并提供了一个功能验证的心血管GxE风险因素目录 疾病。

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.