Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis

J Crohns Colitis. 2022 Jun 4;jjac075. doi: 10.1093/ecco-jcc/jjac075. Online ahead of print.

Abstract

Background and aims: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in pediatric UC and investigated putative pathogenic roles of predictive genes.

Methods: 313 rectal RNA samples from a cohort of newly diagnosed pediatric UC patients (PROTECT) were analyzed 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 analyzed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining.

Results: IL13RA2 was associated with 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 lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (AUC 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.

Conclusion: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve pediatric 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.

Keywords: gene expression array; pediatric inflammatory bowel disease; weighted gene co-expression network analysis.