INTRODUCTION We previously identified 18 CpG methylation biomarkers associated with treatment response to topical corticosteroids (tCS) in eosinophilic esophagitis (EoE). In this study, in an independent cohort, we assessed the validity of these CpG sites as treatment response biomarkers. METHODS DNA was extracted from prospectively biobanked esophageal biopsies from patients with newly diagnosed EoE enrolled in a randomized trial of 2 tCS formulations. Histologic response was defined as <15 eosinophils per high-power field. Pretreatment DNA methylation was assayed on the Illumina Human MethylationEPIC BeadChip. Logistic regression and area under the receiver operating characteristic curve analyses, adjusting for chip, position on the chip, age, sex, and baseline eosinophil count, were computed to test for an association between DNA methylation and treatment response at the 18 previously identified CpG sites. RESULTS We analyzed 88 patients (58 histologic responders, 30 nonresponders), with a mean age of 38 ± 16 years, 64% male, 97% White race. Of the 18 CpG sites, 13 met quality control criteria, and 3 were associated with responder status ( P < 0.012), including sites within UNC5B (cg26152017), ITGA6 (cg01044293), and LRRC8A (cg13962589). All 3 showed evidence of reduced methylation in treatment responders, consistent with the original discovery associations. The predictive probability for nonresponse with all 3 CpG sites was strong (area under the receiver operating characteristic curve = 0.79). DISCUSSION We validated epigenetic biomarkers (CpG methylation sites) for the prediction of tCS response in patients with EoE in an independent population. While not all previously identified markers replicated, 3 demonstrated a relatively high predictive probability for response to treatment and hold promise for guiding tCS treatment in EoE.

中文翻译：

---

用于预测嗜酸性食管炎局部皮质类固醇治疗反应的表观遗传标记的验证。

简介 我们之前鉴定了 18 个 CpG 甲基化生物标志物，这些生物标志物与嗜酸性粒细胞性食管炎 (EoE) 局部皮质类固醇 (tCS) 的治疗反应相关。在这项研究中，我们在一个独立队列中评估了这些 CpG 位点作为治疗反应生物标志物的有效性。方法 从参与 2 种 tCS 制剂随机试验的新诊断 EoE 患者的前瞻性生物库食管活检中提取 DNA。组织学反应定义为每个高倍视野 <15 个嗜酸性粒细胞。在 Illumina Human MmethylationEPIC BeadChip 上检测预处理 DNA 甲基化。计算 Logistic 回归和接受者操作特征曲线下面积分析，调整芯片、芯片上的位置、年龄、性别和基线嗜酸性粒细胞计数，以测试 DNA 甲基化与先前确定的 18 个 CpG 位点的治疗反应之间的关联。结果 我们分析了 88 名患者（58 名组织学反应者，30 名无反应者），平均年龄为 38 ± 16 岁，64% 为男性，97% 为白人。在 18 个 CpG 位点中，13 个符合质量控制标准，3 个与应答者状态相关 ( P < 0.012)，包括 UNC5B (cg26152017)、ITGA6 (cg01044293) 和 LRRC8A (cg13962589) 内的位点。所有三者均显示治疗反应者甲基化减少的证据，与最初发现的关联一致。所有 3 个 CpG 位点无反应的预测概率都很高（受试者工作特征曲线下面积 = 0.79）。讨论 我们在独立人群中验证了表观遗传生物标志物（CpG 甲基化位点）用于预测 EoE 患者的 tCS 反应。虽然并非所有先前确定的标记都可以复制，但 3 表现出对治疗反应的相对较高的预测概率，并有望指导 EoE 中的 tCS 治疗。