Revisiting an Expression Dataset of Discordant Inflammatory Bowel Disease Twin Pairs Using a Mutation Burden Test Reveals CYP2C18 as a Novel Marker.

Juan Du,Jie Yin,Jiawei Zhang,Haojie Du

doi:10.3389/fgene.2021.680125

Abstract

The aim of this study was to investigate the expression features of discordant inflammatory bowel disease (IBD) twin pairs to identify novel molecular features and markers. We collected an expression dataset of discordant twin pairs with ulcerative colitis and performed integrative analysis to identify the genetic-independent expression features. Through deconvolution of the immune cell populations and tissue expression specificity, we refined the candidate genes for susceptibility to ulcerative colitis. We found that dysregulated immune systems and NOD-related pathways were enriched in the expression network of the discordant IBD twin pairs. Among the identified factors were significantly increased proportions of immune cells, including megakaryocytes, neutrophils, natural killer T cells, and lymphatic endothelial cells. The differentially expressed genes were significantly enriched in a gene set associated with cortical and medullary thymocytes. Finally, by combining these expression features with genetic resources, we identified some candidate genes with potential to serve as novel markers of ulcerative colitis, such as CYP2C18. Ulcerative colitis is a subtype of inflammatory bowel disease and a polygenic disorder. Through integrative analysis, we identified some genes, such as CYP2C18, that are involved in the pathogenesis of IBD as well as some candidate therapeutic targets, such as LOXL2.

Highlights

Inflammatory bowel disease (IBD) is a multifactorial disorder that includes three main subtypes, Crohn’s disease (CD), Ulcerative Colitis (UC), and inflammatory bowel disease (IBD) unclassified (IBDU) (Uhlig and Muise, 2017)
Of the fine-mapped genes with at least one variant located in the coding region, six genes, NOD2 (n = 7), IL23R (n = 3), CCDC71 (n = 2), BANK1 (n = 2), MST1 (n = 2), and FUT2 (n = 2) had recurring non-silent variants
We evaluated the potential phenotypes of IBD associated with these fine-mapped candidate genes, and we found that the terms abnormal immunological process, colitis, and inflammation of gastrointestinal or intestinal recurred in

Summary

Introduction

Inflammatory bowel disease (IBD) is a multifactorial disorder that includes three main subtypes, Crohn’s disease (CD), Ulcerative Colitis (UC), and IBD unclassified (IBDU) (Uhlig and Muise, 2017). The phenotypes of these disorders are usually caused by defects in the epithelial barrier and dysregulation in the innate and adaptive immune responses. Genome-wide association studies have refined the candidate genes involved in the pathogenesis of IBDs and have identified candidates in the NOD2-related microbe sensing pathway (Jostins et al, 2012), IL23 driven T-helper cell response (Liu et al, 2015), and autophagy (Schwerd et al, 2017)

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