Investigating the role of aberrant gene regulation in inflammatory bowel disease to understand pathogenesis and help predict relapse

Abstract

IBD is a complex genetic disease characterised by chronic inflammation of the gastro-intestinal tract, with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. Genome wide association studies (GWAS) and meta-analysis have identified >200 genomic IBD susceptibility regions, the most of any complex disease. Here, whole transcriptome sequencing was employed to investigate the role of altered gene expression in intestinal tissue. Differential expression and potential underlying biological pathways were assessed between UC, CD and controls. Furthermore, the effect of indexed IBD risk SNPs on changes in gene expression was investigated. Heterogeneity within the RNA sequenced intestinal biopsy samples was addressed through cellular phenotyping and computational sample deconvolution. Additionally, the presence of a transcriptional signature to predict relapse was investigated. 1,637 transcripts exhibited differential expression at q ≤ 0.05 between the IBD sub phenotypes and controls. Most notably, GLS (Glutaminase), an enzyme which hydrolysis glutamine into glutamate and ammonia. Glutamine is known to be an important energy source for immune and gut mucosal cells. Furthermore, it was observed that these differentially expressed genes significantly perturbed 50 biological pathways. The majority of the identified pathways were involved in processes known to play an important role in IBD: immune regulatory, autophagy and transmembrane signalling. One novel finding was the perturbation of Nicotine degradation pathway II and III within CD patients versus controls and UC patients. Potentially providing insight into the mechanism behind the known opposing effects of smoking on the clinical course of UC and CD patients. Expression of 9 genes located within an IBD loci showed association with an IBD risk SNPs, making them strong candidate genes in IBD pathogenesis and further investigation should be performed.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Natalie Prescott (Supervisor)