Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells

Abstract

The contribution of genetics to the development of gut-related autoimmune diseases such as celiac disease (CeD) and inflammatory bowel diseases (IBDs) is well-established, especially in immune cells, but pinpointing the significance of genetic variants to other cell types is more elusive. Increasing evidence indicates that intestinal epithelial cells are active players in modulating the immune response, suggesting that genetic variants affecting these cells could change cell behavior during disease. Moreover, fine-mapping genetic variants and causal genes to relevant cell types can help to identify drug targets and develop personalized targeted therapies. In this context, we reviewed the functions of genes in disease-associated loci shared by CeD and IBD that are expressed in epithelial cells and explored their potential impacts.

Keywords: celiac disease; epithelial cells; genetics; inflammatory bowel disease.

Figure A1

Immunopathology of CeD (on the left) and IBD (on the right).

Figure A2

Healthy intestinal epithelial structure and immune cell distribution of the (A) small intestine and (B) colon. (C) Junctional proteins connecting two epithelial cells.

Figure 1

Overview of genes in shared loci of CeD, CD, and UC. (A) Selection of genes in disease-associated loci and numbers of overlapping genes across the three diseases. From the 206 overlapping genes, 118 genes are expressed in IECs according to the Gut Cell Atlas [25]. These 118 genes were used for over-representation analysis. (B) Over-representation analysis network plot showing the resulting groups of enriched pathways. Out of the 118 genes, only the genes present in the enriched pathways (n = 38) are depicted in the figure. More detailed information about the selection of these genes is in Appendix C.

Figure 2

Roles of the genes shared between CeD and IBD in epithelial cells. Genes typically considered to have immune functions, e.g., antigen-presentation, T-cell regulation, and cytokine signaling, are also expressed in IECs. Epithelial cells therefore have the ability to modulate immune response and provide co-stimulation to immune cells. Under the right combination of genetics and environmental triggers, the expression of these genes or the function of these proteins can be altered in disease, promoting inflammation. Genes directly involved in IECs homeostasis and barrier integrity can also be affected by genetics and contribute to a defective barrier in disease.