title: Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis.
abstract: OBJECTIVE
  Methotrexate (MTX) is the mainstay treatment for juvenile idiopathic arthritis (JIA), however approximately 30% of children will fail to respond to the drug. Identification of genetic predictors of response to MTX would be invaluable in developing optimal treatment strategies for JIA. Using a candidate gene approach, single nucleotide polymorphisms (SNPs) within genes in the metabolic pathway of MTX, were investigated for association with response to treatment in JIA cases.
  
  
  METHODS
  Tagging SNPs were selected across 13 MTX metabolic pathway genes and were genotyped using Sequenom genotyping technology in subjects recruited from the Sparks Childhood Arthritis Response to Medication Study. Response to MTX was defined using the American College of Rheumatology (ACR) paediatric response criteria and SNP genotype frequencies were compared between the worst and best responders (ACR-Ped70) to MTX. An independent cohort of US JIA cases was available for validation of initial findings.
  
  
  RESULTS
  One SNP within the inosine triphosphate pyrophosphatase gene (ITPA) and two SNPs within 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) were significantly associated with a poor response to MTX. One of the ATIC SNPs showed a trend towards association with MTX response in an independent cohort of US JIA cases. Meta-analysis of the two studies strengthened this association (combined p value=0.002).
  
  
  CONCLUSIONS
  This study presents association of a SNP in the ATIC gene with response to MTX in JIA. There is now growing evidence to support a role of the ATIC gene with response to MTX treatment. These results could contribute towards a better understanding of and ability to predict MTX response in JIA.
authors.affiliation: Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. anne.hinks@manchester.ac.uk
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: Halima
authors.initials: H
authors.lastname: Moncrieffe
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.forename: Simona
authors.initials: S
authors.lastname: Ursu
authors.forename: Sham
authors.initials: S
authors.lastname: Lal
authors.forename: Laura
authors.initials: L
authors.lastname: Kassoumeri
authors.forename: Tracey
authors.initials: T
authors.lastname: Weiler
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009097:Multienzyme Complexes / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D008727:Methotrexate