title: Polymorphisms in genes involved in the mechanism of action of methotrexate: are they associated with outcome in rheumatoid arthritis patients?
abstract: BACKGROUND
  Methotrexate (MTX) is the first-line treatment option for newly diagnosed rheumatoid arthritis (RA) patients. However, 50-70% of the patients respond to treatment and 30% suffer toxicity.
  
  
  OBJECTIVE
  To identify pharmacogenetic markers of outcome in RA patients treated with MTX.
  
  
  METHODS
  We analyzed 27 genetic variants in DHFR, TYMS, MTHFR, ATIC and CCND1 genes.
  
  
  RESULTS
  We included 124 RA patients treated with MTX monotherapy. In multivariate analyses two variants in the MTHFR gene were associated with response, rs17421511 (p = 0.024) and rs1476413 (p = 0.0086), as well as one in the DHFR gene, rs1643650 (p = 0.026). The ATIC rs16853826 variant was associated with toxicity (p = 0.039).
  
  
  CONCLUSIONS
  MTHFR, DHFR and ATIC genetic variants can be considered as pharmacogenetic markers of outcome in RA patients under MTX monotherapy.
authors.affiliation: Genetics Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret, 167, 08025, Barcelona, Spain.
authors.forename: Juliana
authors.initials: J
authors.lastname: Salazar
authors.forename: Patricia
authors.initials: P
authors.lastname: Moya
authors.forename: Albert
authors.initials: A
authors.lastname: Altés
authors.forename: César
authors.initials: C
authors.lastname: Díaz-Torné
authors.forename: Jordi
authors.initials: J
authors.lastname: Casademont
authors.forename: Dacia
authors.initials: D
authors.lastname: Cerdà-Gabaroi
authors.forename: Hèctor
authors.initials: H
authors.lastname: Corominas
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D054316:Biomarkers, Pharmacological; D019938:Cyclin D1 / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D056726:Genetic Association Studies; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; C530104:CCND1 protein, human; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; D019938:Cyclin D1; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D008727:Methotrexate
keywords: 5,10-methylenetetrahydrofolate reductase; 5-aminoimidazole-4-carboxamide ribonucleotide transformylase; ATIC; DHFR; MTHFR; dihydrofolate reductase; methotrexate; rheumatoid arthritis