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.
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 CDpatients (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 CDpatients.
Authors: Ana Teresa P Carvalho; Renata S B Fróes; Barbara C Esberard; Juliana C V C Santos; Davy C M Rapozo; Ana B Grinman; Tatiana A Simão; Pedro Nicolau Neto; Ronir R Luiz; Antonio José V Carneiro; Heitor S P de Souza; Luis Felipe Ribeiro-Pinto Journal: Clinics (Sao Paulo) Date: 2014 Impact factor: 2.365
Authors: Todd D Nebesio; Jamie L Renbarger; Zeina M Nabhan; Sydney E Ross; James E Slaven; Lang Li; Emily C Walvoord; Erica A Eugster Journal: Int J Pediatr Endocrinol Date: 2016-09-26