Gene-Environment Interactions in the Vascular Endothelium

血管内皮的基因-环境相互作用

• 批准号: 10318186
• 负责人: Anthony Scott Findley
• 金额: $ 5.18万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-31 至 2022-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318186
• 关键词: ATAC-seq; Adhesions; Affect; Alleles; Atherosclerosis; Bayesian Modeling; Binding; Binding Sites; Biological Models; Blood Platelets; Caffeine; Cardiovascular Diseases; Cardiovascular system; Catalogs; Cells; Chromatin; Complement; Complex; Confounding Factors (Epidemiology); DNA Sequence; Data; Data Set; Development; Dexamethasone; Disease; Endothelial Cells; Endothelium; Environment; Environmental Exposure; Environmental Risk Factor; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Variation; Genomic approach; Genotype; Haplotypes; Human; Individual; Joints; Lead; Link; Maps; Measures; Meta-Analysis; Methods; Molecular; National Human Genome Research Institute; Pathology; Pathway interactions; Phenotype; Play; Quantitative Trait Loci; Regulatory Element; Research; Risk; Role; Sample Size; Sampling; Site; Testing; Tissues; Tretinoin; Umbilical vein; Untranslated RNA; Variant; Vascular Endothelial Cell; Vascular Endothelium; base; cardiovascular disorder risk; cell type; disease phenotype; exposed human population; falls; functional genomics; gene environment interaction; genetic variant; genome wide association study; genome-wide; individualized prevention; insight; molecular phenotype; novel; personalized medicine; predictive modeling; response; risk variant; trait; transcription factor; transcriptome sequencing; treatment response

Abstract: Gene‐Environment Interactions in the Vascular Endothelium Genome‐wide association studies (GWAS) have identified thousands of genetic variants associated with complex traits. However, only a limited number of environmental factors are measured in GWAS. Thus, some of the genetic effect sizes measured may be underestimated when the underlying environment is composed of many exposures. Controlling for, or accurately measuring, all possible environmental factors in a GWAS setting is a formidable challenge. Instead, molecular phenotypes (gene expression, chromatin accessibility) measured in tightly controlled cellular environments provide a more tractable setting in which to study gene‐environment interactions (GxE) in the absence of other confounding variables. In this proposed research, I will develop methods to investigate causes and consequences of GxE, and I will apply them to analyze the vascular endothelium at the molecular, interindividual, and phenotypic levels. I will use data we have already collected from human umbilical vein endothelial cells (HUVECs) from 17 healthy donors, for 3 treatment conditions (dexamethasone, retinoic acid, and caffeine) and appropriate vehicle‐controls. We genotyped and performed RNA‐seq and ATAC‐seq to model genetic and environmental effects on gene regulation and chromatin accessibility in the vascular endothelium, a common site of pathology in cardiovascular disease (e.g., atherosclerosis). I will first identify transcription factors (TFs) which regulate response to each treatment and predict regulatory variants which affect gene expression in response to treatment. I will then develop a joint allele‐specific expression (ASE) and quantitative trait loci (QTL) mapping approach to experimentally identify GxE‐QTLs in our dataset and validate the computational predictions of the effects of regulatory variants. These variants will be used to fine map and functionally annotate GWAS SNPs associated with cardiovascular disease. Ultimately, findings discovered here will provide insights into the mechanisms for GxE in cardiovascular disease, and the developed methods will be broadly applicable to the study of GxE in other cell types and environmental conditions.

摘要：血管内皮中的基因环境相互作用 全基因组关联研究（GWAS）已经确定了数千种与复合物相关的遗传变异 特质。但是，在GWAS中仅测量了数量有限的环境因素。那是一些遗传效应 当基础环境由许多暴露组成时，可能会低估所测量的尺寸。控制 对于或准确测量，GWAS设置中的所有可能的环境因素都是一个巨大的挑战。反而， 在紧密控制的细胞环境中测量的分子表型（基因表达，染色质可及性） 提供一个更容易研究基因环境相互作用（GXE）的设置，在没有其他的情况下 混淆变量。 在这项拟议的研究中，我将开发研究GXE的原因和后果的方法，我将适用 他们分析分子，个体和表型水平的血管内皮。我将使用我们拥有的数据 已经从17个健康供体的人类脐静脉内皮细胞（HUVEC）中收集到3个治疗条件 （地塞米松，视星酸和咖啡氨酸）以及适当的车辆对照。我们进行了基因分型和进行RNA-Seq 和ATAC -SEQ对血管中基因调节和染色质的可及性建模对遗传和环境影响 内皮是心血管疾病中病理学的常见部位（例如，动脉粥样硬化）。 我将首先确定调节对每种处理的反应并预测调节性的转录因子（TFS） 影响基因表达响应治疗的变体。然后，我将发展一个联合等位基因特异性表达（ASE） 和定量性状位置（QTL）映射方法，以实验性地识别数据集中的GXE -QTL并验证 调节变体影响的计算预测。这些变体将用于细化图和功能 注释与心血管疾病相关的GWAS SNP。最终，这里发现的发现将提供见解 进入心血管疾病中GXE的机制，并且已开发的方法将广泛适用于研究 在其他细胞类型和环境条件下的GXE。