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

GxE 在心血管疾病中的功能基因组学：BPA、邻苯二甲酸盐及其与基因调控的相互作用

基本信息

批准号：
10621140
负责人：
Francesca Luca
金额：
$ 52.2万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-12 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621140
关键词：
ATAC-seq Accounting Affect African American African American population Alleles American American Heart Association Atherosclerosis Binding Biological Assay Blood Vessels Cardiovascular Diseases Cardiovascular Manifestation Cardiovascular system Catalogs Cause of Death Cell Death Cells Cessation of life Chemicals Chromatin Chromosome Mapping Clinical Communities Computing Methodologies Coronary Arteriosclerosis Cosmetics DNA Library Data Development Electrophoretic Mobility Shift Assay Endocrine Disruptors Endothelial Cells Endothelium Environmental Risk Factor European Exposure to Gene Expression Gene Expression Profiling Gene Expression Regulation General Population Genes Genetic Genetic Transcription Genomic approach Heart Diseases Heavy Metals In Vitro Individual Individual Differences Maps Measures Mediating Methods Molecular Nucleotides Outcome Pathway interactions Phenotype Play Population Group Quantitative Trait Loci Regulator Genes Regulatory Element Reporter Reporting Role Sampling Signal Transduction Smooth Muscle Myocytes Statistical Methods Stroke System Testing Transfection Validation Variant Vascular Endothelium Visualization Woman atherosclerosis risk bisphenol A cardiovascular disorder risk cardiovascular health cardiovascular risk factor cell type endothelial dysfunction functional genomics gene environment interaction genetic approach genetic architecture genetic risk factor genetic variant genome wide association study high risk hormonal signals inter-individual variation machine learning method men novel phthalates pollutant response risk variant transcription factor transcriptome sequencing web site

项目摘要

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.

摘要心血管疾病是全球主要的死亡原因，导致超过1790万人死亡到2030年，这一数字预计将增长到2360多万。一些基因和环境因素会增加患心血管疾病的风险。双酚A和邻苯二甲酸酯是两种内分泌这些干扰物广泛存在于日常使用的塑料和化妆品中。这些化学物质诱导内皮细胞- 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。我们建议鉴定与BPA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，对心血管健康的后果。我们将使用RNA-seq和ATAC-seq来表征基因 BPA和邻苯二甲酸酯在血管细胞中诱导的表达和染色质可及性变化。我们将重点非裔美国人供体的血管内皮细胞和平滑肌细胞，这一人群的与欧洲裔美国人相比，遗传学和功能基因组研究。利用分子QTL定位方法，我们将发现新的基因- BPA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遗传学方法来精细映射这些基因-环境相互作用信号，并将它们与相关的心血管疾病的数据。最后，我们建议使用大规模并行报告基因检测来验证这些GxE在基因表达中的作用，并提供了一个功能验证的GxE危险因素目录，疾病