Characterization of Crohn's Disease Subtypes in Treatment-Naïve Paediatric Patients Based on Differential Intestinal Mucosal Transcriptomic Biomarkers

Abstract

Background: Crohn’s disease (CD) is a chronic idiopathic mucosal disease of the gastrointestinal tract that exhibits different phenotypes according to its location. Efforts have been made to differentiate CD subtypes at the genetic level, but the diagnosis of CD subtypes using biomarkers still requires standardization. The aim of this study is to identify differentially expressed genes (DEGs) between the ileum and colon of CD patients using RNA-seq data. Methods: We analysed previously published RNA-seq data from samples collected at diagnostic endoscopy from terminal ileum and colon of 25 treatment-naive paediatric CD patients and 23 controls. We implemented functional profiling and proposed a statistic method for both gene selection and classification using a logistic regression (LR) model. Findings: We found that 550 genes with six different expression types were specifically expressed in CD patients compared to healthy controls (CI 95%, p<0·05): colonic CD genes (CCGs) represented 240 of these genes, and ileal CD genes (ICGs) composed 310. The DEGs were classified into categories such as mitochondrial dysfunction, oxidative phosphorylation, and metabolic pathways. In addition, mitochondrial dysfunction was only detected in the colon of CD patients. Fifty nine genes considered potentially useful for distinguishing Crohn’s disease subtypes were obtained, and average area under curve (AUC) and accuracy were 0·976 and 0·917, respectively. We also validated our method by applying it to an independent cohort of adult CD patients (accuracy = 0·886, AUC = 0·755). Interpretation: Our results show biomarkers for two CD subtypes, which will be useful for the personalized treatment of inflammatory bowel disease (IBD) patients. Funding Statement: This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2019R1I1A2A01060140, 2014M3A9A5034349, 2018M3A9H3023077), and by the KRIBB Research Initiative Program. Declaration of Interests: The authors have no conflicts of interests to declare. Ethics Approval Statement: Mucosal biopsies were collected from colons and terminal ileums (TI) of children newly diagnosed with CD and children without IBD with full ethical approval in the University of Cambridge Department of Paediatrics, as reported in a previous study (EBI study ID: PRJEB24645).