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P677. Gasdermin B (GSDMB) is implicated as a contributor to IBD susceptibility

J. Söderman1, L. Berglind1, S. Almer2, 1Ryhov County Hospital, Division of Medical Diagnostics, Jönköping, Sweden, 2Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden

Background

Most of the hitherto identified inflammatory bowel disease (IBD) susceptibility loci appear to contribute to both of the two main clinical phenotypes, ulcerative colitis (UC) and Crohn's disease (CD). Several genes may reside at each loci. To gain a better insight into the pathogenic mechanisms that underlie IBD, gene expression and genetic variation were investigated at one shared loci (intergenic marker rs2872507).

Methods

Colonic biopsies were obtained from adult patients with UC (n = 18; 20 inflamed and 17 non-inflamed biopsies) or CD (n = 17; 11 inflamed and 17 non-inflamed biopsies), or from non-inflamed non-IBD controls (n = 20; 53 biopsies). Multiple biopsies from single individuals were treated as biological replicates. Gene expression of 12 target genes located within ±195 kbp of rs2872507 was investigated in relation to genotype (Spearman's rank correlation test) and inflammation (Mann–Whitney U test). A Bonferroni corrected P-value <0.0042 was considered significant.

Results

GSDMB expression consistently showed a negative correlation to IBD susceptibility allele load. This was especially evident in non-inflamed colonic mucosa from UC (RS = −0.81) and CD (RS = −0.93) patients, but also in a combined analysis of UC and CD samples from inflamed colonic mucosa (RS = −0.67). No significant correlations were obtained in relation to genotype of non-IBD controls (e.g. GSDMB RS = −0.39, P = 0.090, and GSDMA RS = 0.56, P = 0.0097). Mean expression was significantly decreased (PGAP3, ERBB2, GRB7 and MIEN1) or increased (IKZF3) by a factor two or less in biopsies from inflamed UC colon, when compared to non-inflamed controls and unrelated to genotype. This was also evident in CD, with the exception of MIEN1. CSF3 mean expression was increased at least 80 fold in inflamed biopsies from UC and CD patients.

Conclusion

Considering that the genotype-associated variation in GSDMB expression was not equally evident in non-IBD controls, we propose that the effect of the IBD susceptibility allele is co-dependent on additional factors present in IBD patients, such as modifier genes or altered signalling that parallel IBD presentation. GSDMB (expressed in proliferating epithelial cells / stem cell regions) and GSDMA (apoptotic activity) may be involved in the turnover and differentiation of epithelial cells. Other genes at the locus were differentially expressed in relation to inflammation, and may therefore secondarily contribute to the inflammatory response and disease phenotype.