title: Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis.
abstract: OBJECTIVE
  We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA).
  
  
  METHODS
  Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics.
  
  
  RESULTS
  The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P=0.028, odds ratio=6.90, 95% confidence interval 1.38-34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P=0.029) and rheumatoid factor positivity (P=0.026, odds ratio=2.87, 95% confidence interval 1.11-7.39) were associated with lower efficacy of MTX.
  
  
  CONCLUSIONS
  The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.
authors.affiliation: Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan. m-yanagi@mvi.biglobe.ne.jp
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yanagimachi
authors.forename: Takuya
authors.initials: T
authors.lastname: Naruto
authors.forename: Takuma
authors.initials: T
authors.lastname: Hara
authors.forename: Masako
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Ryoki
authors.initials: R
authors.lastname: Hara
authors.forename: Takako
authors.initials: T
authors.lastname: Miyamae
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Imagawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Kaneko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Goto
authors.forename: Shumpei
authors.initials: S
authors.lastname: Yokota
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008099:Liver / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate