Corticosteroids (CS) effectively induce remission in patients with moderate to severe Crohn's disease (CD). However, CS dependence in children is a significant clinical problem associated with numerous side effects. Identification of molecular markers of CS dependence is of paramount importance. The ABCB1 gene codes for P-glycoprotein, a transporter involved in the metabolism of CS. We examined whether DNA variation in the ABCB1 gene was associated with CS dependency in children with CD.
A retrospective study was carried out in two Canadian tertiary pediatric gastroenterology centers. Clinical information was abstracted from medical charts of CD patients (N = 260) diagnosed with CD prior to age 18 and administered a first course of CS during the 1 year since diagnosis. Patients were classified as CS-dependent if they relapsed during drug tapering or after the end of therapy. DNA was extracted from blood or saliva. Thirteen tagging single nucleotide polymorphisms (tag-SNPs) and a synonymous variation (C3435T) in the ABCB1 gene were genotyped. Allelic, genotype, and haplotype associations were examined using logistic regression and Haploview.
Tag-SNP rs2032583 was statistically significantly associated with CS dependency. The rare C allele of this SNP (odds ratio [OR] = 0.56, 95% confidence interval [CI]: 0.34–0.95, P = 0.029) and heterozygous genotype TC (OR = 0.52, 95% CI: 0.28–0.95, P = 0.035) conferred protection from CS dependency. A three-marker haplotype was significantly associated with CS dependence (multiple comparison corrected P-value = 0.004).
Our results suggest that the ABCB1 gene may be associated with CS dependence in pediatric CD patients. (Inflamm Bowel Dis 2011;)
1Research Centre, Ste-Justine Hospital, Montreal, Quebec, Canada
2Department of Preventive & Social Medicine, University of Montreal, Montreal, Quebec, Canada
3Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
4Department of Medicine, Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada
5Department of Paediatrics, University of Montreal, Montreal, Quebec, Canada
*Reprints: Research Centre, Bureau A-728, Ste-Justine Hospital, 3175 Cote-Sainte-Catherine, Montreal, QC, H3T 1C5 Canada
Received 30 October 2010; Accepted 10 November 2010
Published online 6 January 2011 in Wiley Online Library (wileyonlinelibrary.com).
Dr. Krupoves is supported by a scholarship from the Sainte-Justine Hospital Foundation and by a scholarship of the PhD Program of the University of Montreal. This research was supported by the Canadian Institutes of Health Research (MOP 86609), the Canadian Institutes of Health Research, IBD-Net Grant, Infection and Immunity, and the Sainte-Justine Hospital Foundation.