Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease

Objectives: In pediatric onset of Crohn's disease (CD), corticosteroid dependency (approximately 40%) and resistance (approximately 10%) are significant clinical problems. Given the known effects of the glucocorticoid receptor (GR/NR3C1) gene in corticosteroid metabolism, we investigated whether variation in the gene was associated with corticosteroid response. Methods: A retrospective cohort study was carried out including patients with CD diagnosed before 18 years and treated with a first course of corticosteroids in two Canadian tertiary pediatric gastroenterology clinics. DNA was obtained from blood or saliva. Tagging single nucleotide polymorphisms (SNPs) and functionally important SNPs were genotyped. Allelic, genotype, and haplotype associations between the glucocorticoid receptor SNPs and response to corticosteroids were examined. Results: A total of 296 corticosteroid-resistant, corticosteroids- dependent, and corticosteroid-responsive patients with CD were studied. Of the 12 SNPs examined, four markers, rs6196 [odds ratio (OR)=2.03; 95% confidence interval (CI): 1.03-4.0; P=0.042], rs7701443 (OR=3.43; 95% CI: 1.79-6.57; P=0.042), rs6190 (OR=4.84; 95% CI: 1.70-13.80; P=0.003), and rs860457 (OR=3.43; 95% CI: 1.79-6.57; P<0.001) were associated at the allelic level with corticosteroid resistance. Haplotype analysis of four associated markers revealed associations between two haplotypes and corticosteroid resistance (P values of 0.046 and 0.001). Three SNPs, rs10482682 (OR=1.43; 95% CI: 0.99-2.08; P=0.047), rs6196 (OR=0.55; 95% CI: 0.31-0.95; P=0.024), and rs2963155 (OR=0.64; 95% CI: 0.42-0.98; P=0.039), showed associations under an additive model, whereas rs4912911 (OR=0.37; 95% CI: 0.13-1.00; P=0.03) and rs2963156 (OR=0.32; 95% CI: 0.07-1.12; P=0.047) showed associations under a recessive model with corticosteroid dependence. Two five-marker haplotypes were associated with corticosteroid dependence (P values 0.002 and 0.004). Conclusion: Our results suggest that variations in the GR/NR3C1 gene are associated with corticosteroid resistance and dependency in pediatric-onset CD. Studies are required to replicate these findings and to identify the potentially relevant variants.