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：
10337539
负责人：
Francesca Luca
金额：
$ 52.01万
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/10337539
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 Centers for Disease Control and Prevention (U.S.)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 Regulation General Population Genes Genetic Genetic Transcription Genomic approach Heart Diseases Heavy Metals In Vitro Individual Individual Differences Lead 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 Validation Variant Vascular Endothelium 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

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 Centers for Disease Control and Prevention (U.S.)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 Regulation General Population Genes Genetic Genetic Transcription Genomic approach Heart Diseases Heavy Metals In Vitro Individual Individual Differences Lead 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 Validation Variant Vascular Endothelium 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

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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.

抽象的心血管疾病是全球主要的死亡原因，占死亡人数超过1,790万 2015年每年，这一数字预计到2030年将增长到2360万。环境因素导致心血管疾病风险。双酚A和邻苯二甲酸盐是两个内分泌在日常使用的塑料和化妆品中广泛呈现的破坏者。这些化学物质会诱导内瑟 - 乳细胞死亡，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BPA和邻苯二甲酸盐相互作用并修改血管中基因调节的遗传变异的建议细胞，对心血管健康产生后果。我们将使用RNA-SEQ和ATAC-SEQ表征基因 BPA和血管细胞中邻苯二甲酸酯引起的表达和染色质的可及性变化。我们将集中精力在非裔美国人捐助者的血管内皮和平滑肌细胞上与欧洲裔美国人相比，死于可预防的心血管疾病的风险遗传学和功能基因组研究。使用分子QTL映射方法，我们将发现新的基因 BPA和邻苯二甲酸酯的环境相互作用。然后，我们将使用计算预测和统计遗传学方法可以修饰这些基因 - 环境相互作用信号，并将它们与联合共定位心血管疾病的数据数据。最后，我们建议使用大量平行的记者测定法来验证这些在基因表达中的GXE并提供了功能验证的GXE风险因素的目录疾病。