Since these association studies explain sellectchem only a small part of the genetic contribution in IBD, we took a candidate-gene approach and studied genetic variation in FXR. In the present study, none of the functional or common tagging SNPs proved to be significantly associated with CD or UC. Interestingly, the SNP 518T>C, resulting in the amino acid change M173T, showed an association with the ileocolonic phenotype of CD (Montreal L3)(25) (p=0.015, OR 3.08, 95% CI 1.08�C8.83). The same allele has previously been shown to be associated with intrahepatic cholestasis of pregnancy , and to result in a 60% decrease in transcriptional activity of FXR. Although the M173T was not significantly associated with CD after correction for multiple testing, it may well be that it plays a modifier role in the etiology of CD in conjunction with other genes.
In addition, other weak associations of different tagging SNPs with colonic or ileocolonic phenotypes disappeared after correction for multiple testing. Thus, a primary genetic defect underlying the role of FXR in CD could not be substantiated. Since the functional SNP 518T>C has a very low prevalence, the possibility of a type II error cannot be excluded. Moreover, two of the selected tagging SNP assays failed due to technical reasons. Thus it cannot be excluded that some common SNPs tagging in the remaining 11% of the FXR gene display an association with IBD. Also other explanations accounting for the decreased FXR activity in CD should be considered. This includes the possibility that bile salt uptake in the ileum is reduced, for example due to decreased intestinal transit times.
Indeed, several studies have shown increased fecal excretion of bile salts in patients with CD in clinical remission �C. Another mechanism contributing to this phenomenon could be an intrinsically different regulation of bile salt uptake in the ileum in CD patients . Lastly, reduced FXR target gene expression may be secondary to the reciprocal inhibition of FXR by NF-��B , . It is well established that a range of pro-inflammatory cytokines is upregulated in the mucosa of IBD patients in remission, potentially resulting in downregulated FXR activity, leading to the observed reduced SHP expression in the current study . In conclusion, we found that FXR expression in the ileum is altered in patients with Crohn’s colitis.
This could not be explained by the presence of common SNPs in the FXR gene. Treatment with synthetic FXR agonists may overcome the decrease in FXR activation, possibly resulting in an amelioration of ileocolitis in patients with CD. Supporting Information AV-951 Table S1 qRT-PCR primer list. (DOC) Click here for additional data file.(37K, doc) Table S2 Number of patients and hospitals. (DOC) Click here for additional data file.