Gene-Environment Interactions in the Vascular Endothelium

翻译后摘要：在血管内皮细胞的基因-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杂的 性状然而，只有有限数量的环境因素进行测量，在全球WAS。因此，一些遗传效应 当底层环境由许多暴露组成时，测量的大小可能被低估。控制 准确测量GWAS环境中所有可能的环境因素是一项艰巨的挑战。相反地， 在严格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） 提供了一个更容易处理的环境，在没有其他基因的情况下研究基因与环境的相互作用（GxE）。 混杂变量 在这项拟议的研究中，我将开发方法来调查GxE的原因和后果，我将应用 他们分析血管内皮细胞在分子，个体间，和表型水平。我会用我们掌握的数据 已经从17名健康供体的人脐静脉内皮细胞（HUVEC）中收集了3种治疗条件 （地塞米松、视黄酸和咖啡因）和适当的溶剂对照。我们进行了基因分型和RNA测序， 和ATAC-seq来模拟遗传和环境对血管中基因调控和染色质可及性的影响， 内皮，心血管疾病中常见的病理部位（例如，动脉粥样硬化）。 我将首先鉴定调节对每种治疗的反应的转录因子（TF），并预测调节因子的表达。 影响对治疗作出反应的基因表达的变异。然后，我将开发联合等位基因特异性表达（ASE） 和数量性状基因座（QTL）定位方法，以实验方式确定GxE-QTL在我们的数据集，并验证 调节变体影响的计算预测。这些变体将用于精细映射和功能 注释与心血管疾病相关的GWAS SNPs。最终，这里发现的发现将提供见解， GxE在心血管疾病中的机制，所开发的方法将广泛适用于这项研究 在其他细胞类型和环境条件下的GxE。

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.