title: ABCB1 and ABCC3 gene polymorphisms are associated with first-year response to methotrexate in juvenile idiopathic arthritis.
abstract: OBJECTIVE
  Although methotrexate (MTX) is the most widely prescribed drug in juvenile idiopathic arthritis (JIA), 30% of patients fail to respond to it. To individualize treatment strategies, the genetic determinants of response to MTX should be identified.
  
  
  METHODS
  A cohort of 287 patients with JIA treated with MTX was studied longitudinally over the first year of treatment. MTX response was defined as the American College of Rheumatology pediatric 70 criteria (ACRped70). We genotyped 21 single-nucleotide polymorphisms in 13 genes related to MTX polyglutamylation and to cellular MTX uptake and efflux. Potential associations between ACRped70 and genotypes were analyzed in a multivariate model and corrected for these 3 covariates: disease duration prior to MTX treatment, physician's global assessment of disease activity at baseline, and MTX dose at all study visits.
  
  
  RESULTS
  MTX response was more often achieved by patients variant for the adenosine triphosphate-binding cassette transporter B1 (ABCB1) gene polymorphism rs1045642 (OR 3.80, 95% CI 1.70-8.47, p = 0.001) and patients variant for the ABCC3 gene polymorphism rs4793665 (OR 3.10, 95% CI 1.49-6.41, p = 0.002) than by patients with other genotypes. Patients variant for the solute carrier 19A1 (SLC19A1) gene polymorphism rs1051266 were less likely to respond to MTX (OR 0.25, 95% CI 0.09-0.72, p = 0.011).
  
  
  CONCLUSIONS
  ABCB1 rs1045642, ABCC3 rs4793665, and SLC19A1 rs1051266 polymorphisms were associated with response to MTX in 287 patients with JIA studied longitudinally. Upon validation of our results in other JIA cohorts, these genetic determinants may help to individualize treatment strategies by predicting clinical response to MTX.
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maurits C F J
authors.initials: MC
authors.lastname: de Rotte
authors.forename: Maja
authors.initials: M
authors.lastname: Bulatovic
authors.forename: Marloes W
authors.initials: MW
authors.lastname: Heijstek
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Heil
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Nico M
authors.initials: NM
authors.lastname: Wulffraat
authors.forename: Robert
authors.initials: R
authors.lastname: de Jonge
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018501:Antirheumatic Agents; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C114462:multidrug resistance-associated protein 3