Whole genome transcriptional analysis of intestinal biopsies and blood cells indicate genes involved in antioxidant defense systems, amino acid metabolism and antigen presentation in the pathogenesis of celiac disease.

Abstract

Background: Celiac disease is associated with HLA-risk haplotypes, but non-HLA genes and environmental factors are also linked to disease susceptibility. In this study, we explore the molecular pathways involved in celiac disease by analyzing the differential expression of genes in both the gut and peripheral blood across various celiac disease phenotypes.

Methods: Whole genome RNA sequencing was performed on 283 samples from intestinal mucosa and peripheral blood from 72 cases with either active, potential, or treated celiac disease and 73 disease controls. Enrichr pathway analysis of top differentially expressed genes was performed.

Results: Overall, 7565 genes in intestinal biopsies and 542 genes in blood samples were differentially expressed between cases and controls. Compared with controls, immunoglobulin heavy variable 5-51 (IGHV5-51) (p = 1.05 × 10^-14) and tissue transglutaminase (TGM2) (p = 5.29 × 10^-10), encoding for TG2, the main autoantigen in celiac disease, were two of the top up-regulated genes in intestinal biopsies from celiac cases. TGM2 was also slightly upregulated in blood cells from cases with active disease compared with controls (p = 0.05). The topmost differentially expressed genes in peripheral blood were HLA-DQB1, HLA-DQB2, and GSTM1. Among pathways identified containing transcriptionally differentiated genes were antioxidant defense systems (e.g., nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione, ergothioneine, and peroxisome metabolism), as well as MHC class 1 antigen presentation, amino acid transport, mTORC1, bilirubin and lipid metabolism, liver homeostasis, the complement system, and interferon signaling.

Conclusions: Differentially expressed genes in cases and controls indicate crosstalk between molecular pathways involved in antioxidant defense, immune regulation, and nutrient signaling in the pathogenesis of celiac disease.