Division of Gastroenterology, Hepatology and Nutrition.
Division of Pediatric Gastroenterology, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
J Crohns Colitis. 2022 Nov 23;16(11):1735-1750. doi: 10.1093/ecco-jcc/jjac075.
We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes.
In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining.
IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining.
Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13Rɑ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.
我们旨在确定靶向基因表达谱是否可预测儿科溃疡性结肠炎[UC]的临床结局，并探讨预测基因的潜在致病作用。
共对来自一组新诊断的儿科 UC 患者（PROTECT）的 313 个直肠 RNA 样本进行实时 PCR 微流控阵列分析，以检测 1 型、2 型和 17 型炎症基因的表达。通过逻辑回归评估表达与临床结局之间的关联。使用现有的 RNA 测序（RNA-seq）数据集和组织免疫染色进一步分析鉴定的预后标志物。
IL13RA2 与第 52 周无皮质类固醇缓解（CSFR）的可能性较低相关（p=0.002）。包括 IL13RA2 和仅基线临床参数的模型与需要第 4 周缓解状态的既定临床模型一样准确。RORC 与第 52 周行结肠切除术的可能性较低相关。包括 RORC 和 PUCAI 的模型可预测第 52 周的结肠切除术（接受者操作特征曲线下面积 0.71）。批量 RNA-seq 鉴定出 IL13RA2 和 RORC 是与细胞外基质和固有免疫反应以及脂质代谢和微绒毛组装相关的 UC 结局相关表达网络中的枢纽基因。成人 UC 单细胞 RNA-seq 数据显示，IL13RA2 和 RORC 共表达基因分别定位于炎症成纤维细胞和未分化上皮细胞，蛋白免疫染色也支持这一点。
直肠黏膜免疫基因表达的靶向评估可预测治疗初治的儿科 UC 患者的 52 周 CSFR。有必要进一步探索 IL-13Rɑ2 作为 UC 的治疗靶点，并进一步研究 RORC 在 UC 发病机制中的上皮特异性作用。
