Gene-Environment Interactions in the Vascular Endothelium

摘要：血管内皮细胞中的基因-环境相互作用 全基因组关联研究已经确定了数千种与复合体相关的遗传变异。 特征。然而，只有有限数量的环境因素在全球气候变化系统中被衡量。因此，一些遗传效应 当基础环境由许多曝光组成时，测量的大小可能被低估。控制 对于或准确地测量全球气候变化环境中的所有可能的环境因素是一项艰巨的挑战。相反， 在严格控制的细胞环境中测量分子表型(基因表达、染色质可及性) 为研究基因-环境相互作用(GxE)提供了一个更容易处理的环境 令人困惑的变量。 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 他们在分子、个体和表型水平上分析血管内皮细胞。我会用我们掌握的数据 已从17名健康供者的人脐静脉内皮细胞(HUVECs)中采集，用于3种治疗条件 (地塞米松、维甲酸和咖啡因)和适当的车辆控制。我们进行了基因分型和rna-seq。 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。 血管内皮细胞，心血管疾病(如动脉粥样硬化)的常见病理部位。 我将首先确定调节对每个治疗的反应的转录因子(TF)，并预测调节 影响治疗反应的基因表达的变种。然后我将开发一个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，在我们的数据集中实验地识别GxE-QTL，并验证 对调控变种影响的计算预测。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GWASNPs。最终，这里发现的结果将提供洞察力 GxE在心血管疾病中的作用机制，所开发的方法将广泛适用于这项研究 GxE在其他细胞类型和环境条件下的表达。

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.