Exploring celiac disease candidate pathways by global gene expression profiling and gene network cluster analysis

Babajan Banaganapalli,Haifa Mansour,Ramu Elango,Omar I Saadah,Aftab Ahmad,Jumana Yousuf Al-Aama,Noor Ahmad Shaik,Arwa Mastoor Alharthi,Arif Mohammed,Nada Mohammed Aljuaid,Khalidah Khalid Nasser

doi:10.1038/s41598-020-73288-6

Abstract

Celiac disease (CeD) is a gastrointestinal autoimmune disorder, whose specific molecular basis is not yet fully interpreted. Therefore, in this study, we compared the global gene expression profile of duodenum tissues from CeD patients, both at the time of disease diagnosis and after two years of the gluten-free diet. A series of advanced systems biology approaches like differential gene expression, protein–protein interactions, gene network-cluster analysis were deployed to annotate the candidate pathways relevant to CeD pathogenesis. The duodenum tissues from CeD patients revealed the differential expression of 106 up- and 193 down-regulated genes. The pathway enrichment of differentially expressed genes (DEGs) highlights the involvement of biological pathways related to loss of cell division regulation (cell cycle, p53 signalling pathway), immune system processes (NOD-like receptor signalling pathway, Th1, and Th2 cell differentiation, IL-17 signalling pathway) and impaired metabolism and absorption (mineral and vitamin absorptions and drug metabolism) in celiac disease. The molecular dysfunctions of these 3 biological events tend to increase the number of intraepithelial lymphocytes (IELs) and villous atrophy of the duodenal mucosa promoting the development of CeD. For the first time, this study highlights the involvement of aberrant cell division, immune system, absorption, and metabolism pathways in CeD pathophysiology and presents potential novel therapeutic opportunities.

Highlights

Celiac disease (CeD) is a gastrointestinal autoimmune disorder, whose specific molecular basis is not yet fully interpreted
Gluten-free diet versus in-vitro gliadin challenge analysis showed that global gene expression changes were less than 1.5 folds and insignificant, they were omitted from further analysis
By integrating gene expression data with protein interaction network concepts, this study has identified the contribution of dysregulated immune system genes in the intestinal mucosa of CeD

Summary

Introduction

Celiac disease (CeD) is a gastrointestinal autoimmune disorder, whose specific molecular basis is not yet fully interpreted. In this study, we compared the global gene expression profile of duodenum tissues from CeD patients, both at the time of disease diagnosis and after two years of the gluten-free diet. Genome-wide association studies (GWAS) conducted on CeD have discovered that non-HLA genes like IL2 and IL21, which are involved in T cell maturation, can modulate the risk of disease development in genetically susceptible individuals[12,13,14]. Combining the gene expression measurements with protein–protein interactions (PPIs) and pathway analysis will provide a deeper insight into gene expression induced CeD development We conducted this first systems biology study to compare the gene expression profile of duodenum tissue samples of celiac patients at diagnosis and after restricted gluten-free diet. This study characterized the protein interactions and molecular pathways involving several differentially expressed genes (DEGs) and provided a global view of gene expression changes critical to CeD pathogenesis, which presents potential therapeutic avenues for future research

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Conclusion