Consensus Weighted Gene Co-expression Network Analysis demonstrates aberrations in folding of actin by CCT/TriC chaperonin family in Celiac disease

Abstract

Background: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten. Almost 90% of CeD patients have HLA-DQ2 or -DQ8 haplotypes. As a high proportion of first-degree relatives (FDRs) of CeD patients have the same haplotype, it is assumed that they are at a higher risk of disease development than the general population. Nevertheless, the prevalence of CeD among FDRs is considerably low (7.5%). Methods: In order to figure out this discrepancy, a microarray dataset of intestinal mucosal biopsies from CeD, FDR, and control groups was reanalyzed, and gene co-expression network using WGCNA was constructed. The differentially expressed genes in the opposite modules from the consensus analysis were applied for functional enrichment analysis. Results: WGCNA analysis identified 10 consensus modules in both CeD and FDR groups, including 5 modules with opposite correlation. Among the genes of opposing modules, 159 of them were identified as commonly differentially expressed genes with an adjusted p-value< 0.05 between FDR and CeD groups. Functional enrichment analysis revealed the significant contributions of these genes in host energy metabolism, programmed cell death, antigen cross presentation, and actin folding. In a deep view to the relation of actin folding to celiac disease occurrence, it was found that misfolding of actin and presentation of anti-actin antibodies occur in CeD patients. The current study reports that this pathway is oppositely regulated in FDR group and this might be a trigger for celiac manifestation. Conclusions: The consensus signaling pathways with opposing expression patterns identified in this study give us a clue about the gene circuits that are dysregulated in celiac patients. Considering the prominent relation of actin folding to disease occurrence and its opposite manner in celiac patients and healthy individuals, it is proposed that targeting CCT/TriC chaperonin family might result in a reduction of misfolded actin and the production of autoantibodies.