CANCELLED - Celiac disease associated genetics points to a major role of Interferon gamma signalling and identifies TRAFD1 as master regulator in disease

Status: This talk is in preparation - details may change
Status: This talk has been cancelled

Celiac disease (CeD) is a complex T cell–mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signalling and T cell activation pathways. 51 of these genes are targets of known drug compounds, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 129 gene-combinations that were affected by our CeD-prioritized genes in trans. Notably, 40 of these trans-mediated genes appear to be under control of one master regulator, TRAFD1, and were found to be involved in IFN signalling and MHC I antigen processing/presentation. We then performed in vitro experiments that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy has confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and the IFNsignalling and MHC I antigen processing pathways, both major players of immune activation and CeD pathogenesis. Our next steps will be to test the role of TRAFD1 in a novel, human model system of the intestinal barrier, the gut-on-chip.