Gene-environment interaction pathways in rheumatoid arthritis

摘要 共享表位(SE)编码的人类白细胞抗原-DRB1等位基因是严重类风湿性关节炎的单一最强遗传风险。在……里面 除了遗传易感性外，接触环境污染物，如二恶英类化合物，以及 烟草烟雾强烈影响类风湿性关节炎的风险和严重性。此外，SE与烟草烟雾之间的相互作用 暴露已被证明以倍增的、剂量依赖的方式增加类风湿关节炎的风险。这个 这种流行病学观察到的基因-环境相互作用的机制基础尚不清楚。 我们最近发现了核因子-kB介导的SE和芳香烃受体之间的串扰 (AHR)在体外对破骨细胞分化和Th17极化产生协同作用的途径。 给携带人类SE编码等位基因的转基因小鼠注射AhR途径激动剂可导致 关节炎严重程度、骨质破坏、破骨细胞和IL17表达过多的强劲增长 关节炎小鼠炎症关节和引流淋巴结中的细胞。因此，我们已经发现了一个以前的 未知的基因-环境相互作用机制。 这里提出的研究将集中于对新发现的协同作用的详细描述 确定SE配体、AhR激动剂及其组合的转录效应。生理学 这些发现的相关性将在活体小鼠系统中得到证实，并得到人类翻译的证实。 学习。拟议的研究将有以下具体目标： 使用rna-seq方法识别和绘制协同途径图。 以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激动剂的小鼠的相互作用途径 用于确定人类细胞系和原代细胞中的途径相互作用 当成功完成后，拟议的项目将确定新的致病机制和 类风湿关节炎的疾病风险和严重程度标记物。这些发现将为识别新的 可以在未来的研究项目中追求的治疗目标。

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.