Gene-environment interaction pathways in rheumatoid arthritis

摘要 共享表位（SE）编码HLA-DRB 1等位基因赋予严重RA的单一最强遗传风险。在 除了遗传易感性，暴露于环境污染物，如二恶英类化合物， 吸烟强烈影响RA的风险和严重程度。此外，SE和烟草烟雾之间的相互作用 暴露已显示以倍增的、剂量依赖性的方式增加RA的风险。的 这种流行病学上观察到的基因-环境相互作用的机制基础是未知的。 我们最近发现了一个NF-κ B介导的串扰之间的SE和芳烃受体 (AhR)导致体外破骨细胞分化和Th 17极化的协同效应的途径。 对携带人SE编码等位基因的转基因小鼠施用AhR途径激动剂导致 关节炎严重程度、骨破坏和破骨细胞和IL 17表达的过度增加 关节炎小鼠发炎关节和引流淋巴结中的细胞。因此，我们发现了一个以前 基因与环境相互作用的未知机制。 这里提出的研究将集中在新发现的协同作用的详细表征， 定义了SE配体、AhR激动剂及其组合的转录组学效应。生理 这些发现的相关性将在体内小鼠系统以及人类翻译系统中得到证实。 问题研究拟议的研究将有以下具体目标： 使用RNA-seq方法鉴定和绘制协同途径 确定相互作用对染色质可及性的影响，并验证转录因子 激活 验证暴露于AhR激动剂的小鼠中的相互作用途径 确定人类细胞系和原代细胞中的通路相互作用 成功完成后，拟议项目将确定新的致病机制， 疾病风险和严重程度标志物。这些发现将为识别新的 在未来的研究项目中可以追求的治疗目标。

ABSTRACT Shared epitope (SE)-coding HLA-DRB1 alleles confer the single strongest genetic risk for severe RA. In addition to genetic predisposition, exposure to environmental pollutants, such as dioxin-like compounds, and tobacco smoke strongly affect RA risk and severity. Furthermore, interactions between SE and tobacco smoke exposure has been shown to increase the risk for RA in a multiplicative, dose-dependent fashion. The mechanistic basis of this epidemiologically observed gene-environment interaction is unknown. We have recently uncovered an NF-kB-mediated crosstalk between the SE and aryl hydrocarbon receptor (AhR) pathways that lead to synergistic effects on osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction and overabundance of osteoclasts and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, we have uncovered a previously unrecognized mechanism of gene-environment interaction. The studies proposed here will focused on detailed characterization of the newly uncovered synergism by defining the transcriptomic effects of the SE ligand, AhR agonists, and their combination. The physiologic relevance of the findings will be corroborated in in vivo mouse systems, as well as by human translational studies. The proposed research will have the following specific aims:  To identify and map the synergistic pathways using an RNA-seq approach  To determine the effect of the interaction on chromatin accessibility and validate transcription factor activation  To validate interacting pathways in mice exposed to AhR agonists  To determine pathway interactions in human cell lines and primary cells When successfully completed, the proposed project will have identified new pathogenic mechanisms and disease risk and severity markers in RA. Such findings will open the door to identification of new therapeutic targets that could be pursued in future research projects.