However, c-myc and CCDN1 did sellectchem not correlate to Villin, SI, FXR or SHP expression in any of the groups (data not shown). Figure 1 FXR target gene expression is decreased in patients with Crohn’s disease. Figure 2 FXR and SHP correlate with Villin in healthy controls but not in Crohn’s disease patients. Assessment of FXR genetic variation in IBD patients A total of 2355 IBD patients and 853 controls were genotyped with seven tagging SNPs and two functional SNPs in FXR. None of the functional SNPs was associated with the presence of IBD. One of the tagging SNPs, however, displayed a significant association with IBD (rs12313471, p=0.03, OR 1.32, 95% CI 1.02�C1.71; Table S4). CD (n=1162) and UC patients (n=1193) were also separately compared to the 853 healthy controls.
The same tagging SNP (rs12313471) was associated with UC (p=0.049, OR 1.32, 95% CI 1.00�C1.76; Table S5). None of the SNPs was associated with CD (Table S6). None of the above described associations remained significant after Bonferroni correction for multiple testing. Subgroup analyses Phenotypic information on the localization of the disease was present for 1132 of 1162 (97.4%) patients with CD. We analyzed whether polymorphisms of FXR were associated with CD location using the Montreal classification [25]. Patients with L1 (terminal ileum location; n=257), L2 (colonic location; n=295) and L3 (ileocolonic location; n=580) were compared to CD patients with other disease locations. Two tagging SNPs displayed a significant association with ileal CD (L1; rs11110390, p=0.03, OR 1.26, 95% CI 1.02�C1.
55 and rs4764980, p=0.03, OR 0.80, 95% CI 0.65�C0.98, Table S7). None of the SNPs was associated with colonic CD (L2, Table S8). Two SNPs showed a significant association with ileocolonic CD (L3), namely the functional SNP 518T>C (p=0.015, OR 3.08, 95% CI 1.08�C8.83) and one of the tagging SNPs (rs10860603, p=0.013, OR 1.39, 95% CI 1.07�C1.81; Table S9). None of these subgroup analyses, however, remained significant after Bonferroni correction for multiple testing. Discussion Although the exact etiology of IBD is not completely understood, several lines of evidence point to an impaired intestinal barrier function and an abnormal immune response in genetically susceptible hosts.
Recently, we reported that activation of the nuclear receptor FXR prevents inflammation in animal models of IBD with improvement of colitis symptoms, preservation of the Batimastat intestinal epithelial barrier function and reduction of goblet cell loss [17]. Furthermore, a negative cross-talk between FXR and the inflammatory response at the intestinal level was demonstrated [19], probably contributing to an attenuated intestinal inflammatory status. In the present study, we showed that ileal mRNA expression of the FXR target gene SHP is markedly reduced in Crohn’s colitis patients, whereas FXR expression remained unchanged. This suggests that FXR activity is decreased in this IBD subtype.