Gene Expression-Genotype Analysis ImplicatesGSDMA,GSDMB, andLRRC3Cas Contributors to Inflammatory Bowel Disease Susceptibility

Abstract

To investigate the biological foundation of the inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease, susceptibility locus rs2872507, we have investigated the expression of 13 genes using ileal and colonic biopsies from patients with IBD (inflamed and noninflamed mucosa) or from individuals without IBD (noninflamed mucosa). The susceptibility allele was consistently associated with reduced expression ofGSDMB(P= 4.1 × 10−3–7.2 × 10−10). The susceptibility allele was also associated with the increased expression ofGSDMA(P= 1.6 × 10−4) andLRRC3C(P= 7.8 × 10−6) in colon tissue from individuals without IBD and with the reduced expression ofPGAP3(IBD;P= 2.0 × 10−3) andZPBP2(Crohn’s disease;P= 7.7 × 10−4) in noninflamed ileum. Inflammation resulted in the reduced colonic expression ofERBB2,GRB7,MIEN1, andPGAP3(P= 1.0 × 10−4–1.0 × 10−9) and the increased colonic expression ofIKZF3andCSF3(P= 2.4 × 10−7–3.5 × 10−8). Based on our results and published findings onGSDMA,GSDMB,LRRC3C, and related proteins, we propose that this locus in part affects IBD susceptibility via effects on apoptosis and cell proliferation and believe this hypothesis warrants further experimental investigation.