Associations between variants in the ABCB1 (MDR1) gene and corticosteroid dependence in children with Crohn's disease

Abstract

Background: 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. Methods: 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. Results: 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). Conclusions: Our results suggest that the ABCB1 gene may be associated with CS dependence in pediatric CD patients. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.