Gastroenterology

Gastroenterology

Volume 130, Issue 2, February 2006, Pages 341-348
Gastroenterology

Clinical–alimentary tract
The Pregnane X Receptor Locus Is Associated With Susceptibility to Inflammatory Bowel Disease

https://doi.org/10.1053/j.gastro.2005.12.008Get rights and content

Background & Aims: The pregnane X receptor (PXR) regulates an array of genes involved in the response to xenobiotics. Evidence from several studies suggests that xenobiotic metabolism may play a role in inflammatory bowel disease (IBD) and that low levels of PXR may be associated with disease expression. The aim of this study was to investigate the association of functional polymorphisms of the PXR encoding gene (NR1I2) with disease in IBD populations. Methods: This was a case-control study examining 8 NR1I2 single nucleotide polymorphisms (SNPs) previously associated with altered activity of PXR-regulated genes in an Irish cohort including 422 patients with IBD and 350 ethnically matched controls. Results: We showed significant associations of NR1I2 with IBD, Crohn’s disease (CD), and ulcerative colitis (UC) groups compared with a control population for SNPs −23585 (IBD: P = .000008; odds ratio [OR], 1.62; 95% confidence interval [CI], 1.31–2.00) and −24381 (IBD: P = .0002; OR, 1.50; 95% CI, 1.21–1.84). SNPs 7635 (P = .0008) and 8055 (P = .007) were found to be associated with IBD and CD but not UC. Risk of IBD is strongly correlated to genotype at these sites, especially for the −25385CC genotype (P = .00001; OR, 2.92; 95% CI, 1.87–4.66). We also show specific correlations of IBD phenotype with genotypes and haplotypes in the patient group. Conclusions: These results show that genetic variation in the PXR encoding gene, which has been associated with altered activity of PXR, is strongly associated with susceptibility to IBD, CD, and UC.

Section snippets

Study Subjects

The study population consisted of 422 unrelated patients with IBD from clinics in St James’s Hospital, St Vincent’s Hospital, and the Adelaide and Meath Hospital in Ireland and a random sample of ethnically matched but otherwise unselected controls (n = 350). Both patients and controls were Irish white subjects. The study was approved by the institutional ethics review committees, and all patients gave informed consent. Patients were diagnosed and classified by standard endoscopic, histologic,

Quality Control

Approximately 8.5% of samples were retyped anonymously for each assay as a routine quality control to assess accuracy of genotyping. A maximum of 1 genotype differed in any of the assays, and it was a different individual in each case. The restriction fragment length polymorphism assay for the 7635 SNPs also detected only 1 data point error compared with the Amplifluor 7635 SNP assay. The overall genotype error rate was slightly less than 1%, and allele miscall frequency was 0.48%. No site

Discussion

This study showed an association between genetic variation in NR1I2 and IBD. The minor allele frequencies of −25385, −24381, and 7635 were significantly reduced in patients with IBD compared with healthy controls. These SNPs have previously been reported to have functional consequences for PXR activity. Their genotype distributions in the disease populations are compatible with a functional role in IBD. In general, there is an increasing likelihood of IBD with increasing dosage of the

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    Supported by the Irish Health Research Board, the Health Education Authority Programme for Research in Third Level Institutions, and Hitachi Europe, Ltd. R.M. is a Wellcome Trust/ Health Research Board lecturer. A.-C.W. was supported by the Swedish Society of Medicine and the Swedish Research Council (grant K2003-31X-14878-01A). This project was facilitated by the European Commission-funded thematic research network, Steroids in Health and Disease (Eurosterone; QLR1-CT-1999-00762).

    C.M.S.’s current affiliation is: Department of Hepatology, Beaumont Hospital, Beaumont, Dublin, Ireland.

    This work was jointly supervised by D.K. and R.M.

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