Molecular and epigenetic predictors and mechanisms of treatment response to topical steroids in eosinophilic esophagitis

局部用类固醇激素治疗的分子和表观遗传学预测因子及机制 嗜酸性食管炎 摘要 嗜酸性粒细胞性食管炎（EoE）是一种慢性免疫介导的疾病， 嗜酸性粒细胞进入食管粘膜，导致吞咽困难、进行性食管狭窄和食物中毒。 嵌塞其发病率和患病率正在急剧上升，EoE已迅速成为一个主要原因 上消化道疾病尽管这种重要性日益增加，但关于理想的许多情况仍不为人所知。 我们无法预测哪些患者会对特定治疗产生反应。从业者 必须令人沮丧地使用试验和错误，患者受到昂贵的治疗和侵入性和昂贵的 在不知道他们个人可能作出反应的情况下，吞咽时/局部 皮质类固醇是目前治疗EoE的主要药物，无反应是常见的， 50%的患者。确定哪些患者不太可能有组织学反应将允许 个性化治疗，但没有预测已被验证用于临床使用。我们已经开始解决 这一主要的知识差距，现在有两种新技术的有希望的数据。首先是差异化 基因表达的相关性，其中在应答者之间评估基因对之间的相关性， 无应答者。我们确定了一个22个基因模块，其中有显着较高的差异相关性， 治疗前基线无应答者，并确定了潜在相关的miRNA途径 监管部门第二种是表观遗传甲基化，我们在18个CpG位点发现了差异甲基化 当比较基线时的治疗应答者和无应答者时。因为微分相关和 甲基化都意味着生物途径的差异调节，它们可以提供高度需要的信息， 关于无反应的分子机制，也可能产生新的治疗靶点。的总目标 本研究旨在验证这两种新方法在预测EoE治疗反应方面的有效性， 这些结果研究无反应的分子机制，具体目的是1）验证前， 用于预测局部类固醇无反应的治疗差异相关基因表达模块 EoE患者;和2）验证治疗前表观遗传甲基化谱用于预测EoE局部 EoE患者类固醇无反应。为了实现这些目标，我们将对 来自由PI（R 01）进行的NIH资助的随机临床试验的丰富临床和生物样本集 DK 101856），比较了布地奈德与氟替卡松对EoE的初始治疗。这个创新的假设- 驱动，严格设计的研究将由现有的多学科团队进行， EoE、临床试验、流行病学、遗传学、统计学和转化科学方面的专业知识。本研究将 对EoE的局部类固醇治疗有重大影响。确定反应的预测因素是提供 有效和个性化的疾病管理以及了解无反应的机制， 由于目前临床上还没有使用预测因子，我们的研究结果将大大改善病人的护理。

Molecular and epigenetic predictors and mechanisms of treatment response to topical steroids in eosinophilic esophagitis ABSTRACT Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to dysphagia, progressive esophageal stenosis, and food impaction. The incidence and prevalence are rising dramatically, and EoE has rapidly become a major cause of upper gastrointestinal morbidity. Despite this increasing importance, much is unknown about the ideal approach to treatment, and we cannot predict which patients will respond to specific treatments. Practitioners must frustratingly use trial and error, and patients are subjected to expensive therapies and invasive and costly follow-up procedures without knowing their individual likelihood of response. While swallowed/topical corticosteroids are currently a mainstay of therapy for EoE, non-response is common and can be seen in up to 50% of EoE patients. Identifying which patients are less likely to have a histologic response would allow for personalization of therapy, but no predictors have been validated for clinical use. We have begun to address this major knowledge gap, and now have promising data for two novel techniques. The first is differential correlation of gene expression, where the correlation between gene pairs is assessed between responders and non-responders. We identified a 22 gene module where there was significantly higher differential correlation in non-responders at baseline prior to treatment, and also identified potential associated miRNA pathway regulators. The second is epigenetic methylation, where we identified differential methylation at 18 CpG sites when comparing treatment responders and non-responders at baseline. Because differential correlation and methylation both imply differential regulation of biologic pathways, they can provide highly needed information about molecular mechanisms of non-response, and also may yield new treatment targets. The overall goal of the proposed study is to validate these two novel methods for prediction of treatment response in EoE and use these results to investigate molecular mechanisms of non-response The specific aims are to 1) validate a pre- treatment differential correlation gene expression module for prediction of topical steroid non-response in patients with EoE; and 2) to validate a pre-treatment epigenetic methylation profile for prediction of topical steroid non-response in patients with EoE. To achieve these aims, we will perform a secondary analysis of a rich clinical and biosample set from an NIH-funded randomized clinical trial conducted by the PI (R01 DK101856) that compared budesonide to fluticasone for initial treatment of EoE. This innovative, hypothesis- driven, and rigorously designed study will be conducted by an existing multidisciplinary team with recognized expertise in EoE, clinical trials, epidemiology, genetics, statistics, and translational science. This study will have a major impact on topical steroid treatment in EoE. Identifying predictors of response is key to delivering effective and individualized disease management as well as understanding mechanisms of non-response, and because no predictors are currently used clinically, our results will greatly improve patient care.