Investigation of associations between the pregnane-X receptor gene (NR1I2) and Crohn's disease in Canadian children using a gene-wide haplotype-based approach

Abstract

Background: The pregnane-X-receptor (PXR) is involved in the metabolism and detoxification of numerous xenobiotics and is critical for maintaining intestinal integrity. The NR112 gene encoding PXR may confer susceptibility for Crohn's disease (CD) but evidence for associations is conflicting. We investigated whether the NR112 gene was associated with susceptibility for pediatric CD. Methods: A case-control and family-based (case-parent) study was carried out at 3 inflammatory bowel disease (IBD) clinics across Canada. Confirmed cases of CD <20 years were diagnosed using standard criteria. For determination of gene associations parents of the cases and unrelated controls were evaluated. Clinical phenotypes were established based on the Montreal Classification scheme. Eight tag-SNPs (tag-single nucleotide polymorphisms) across the gene were genotyped for allelic or genotypic associations. Results: A total of 270 CD cases, 336 controls, and 395 parents were studied. The mean age (±SD) of the cases was 12.1 (±3.5) years of age. Most cases were male (56.3%), had disease location L3±L4 (58.1%), and an inflammatory phenotype B1±p (88.4%) at diagnosis. For 7 SNPs single SNP analysis using case-control or case-parent data did not reveal associations with development of CD and none of the SNPs were significantly associated with disease location or disease behavior at diagnosis. One SNP rs2461823 (P = 0.05) was nominally associated with CD. No overall haplotype association (omnibus P-value = 0.61) or associations with individual haplotypes was evident. Conclusions: Our gene-wide analysis in a pediatric cohort using both the case-control and case-parent designs suggests that the NR112 gene is not associated with CD in Canadian children. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.