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

Alfreda Krupoves, David MacK, Colette Deslandres, Ernest Seidman, Devendra K. Amre

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)454-460
Number of pages7
JournalPharmacogenetics and Genomics
Volume21
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

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Glucocorticoid Receptors
Crohn Disease
Adrenal Cortex Hormones
Odds Ratio
Confidence Intervals
Genes
Single Nucleotide Polymorphism
Haplotypes
Gastroenterology
Saliva
Cohort Studies
Retrospective Studies
Genotype

Keywords

  • corticosteroids
  • Crohn's disease
  • glucocorticoid receptor
  • NR3C1
  • pediatric
  • pharmacogenetics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease. / Krupoves, Alfreda; MacK, David; Deslandres, Colette; Seidman, Ernest; Amre, Devendra K.

In: Pharmacogenetics and Genomics, Vol. 21, No. 8, 08.2011, p. 454-460.

Research output: Contribution to journalArticle

Krupoves, Alfreda ; MacK, David ; Deslandres, Colette ; Seidman, Ernest ; Amre, Devendra K. / Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease. In: Pharmacogenetics and Genomics. 2011 ; Vol. 21, No. 8. pp. 454-460.
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title = "Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease",
abstract = "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.",
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T1 - Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease

AU - Krupoves, Alfreda

AU - MacK, David

AU - Deslandres, Colette

AU - Seidman, Ernest

AU - Amre, Devendra K.

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

KW - corticosteroids

KW - Crohn's disease

KW - glucocorticoid receptor

KW - NR3C1

KW - pediatric

KW - pharmacogenetics

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