title: Influence of MTHFR C677T polymorphism on methotrexate monotherapy discontinuation in rheumatoid arthritis patients: results from the GAPAID European project.
abstract: OBJECTIVE
  Methotrexate (MTX) is the most widely prescribed drug for rheumatoid arthritis (RA) patients, but 45% of them discontinue therapy within two years, either due to inefficacy or toxicity. Several authors have reported contradictory results related to C677T polymorphism in the MTHFR gene and response to MTX in RA. The purpose of this study was to further explore this genotype-response association in a European RA population.
  
  
  METHODS
  This retrospective longitudinal study included a total of 269 RA patients from Italy and Hungary, of whom 73.2% had available data on MTX treatment (197 patients). C677T polymorphism (rs1801133) was genotyped by quantitative PCR using TaqMan assays. Genotype association analysis and Kaplan-Meier method were used for statistical comparisons between patients continuing and patients who abandoned MTX treatment.
  
  
  RESULTS
  A total of 85 out of the 197 RA patients (43%) abandoned MTX treatment by the time of analysis. No significant genotype-MTX discontinuation association was found for the overall population, either at the end of the study (p=0.375), or during the follow-up (p=0.324). When the analysis was restricted to the 68 patients on MTX monotherapy, a borderline association (OR 3.15, 95% CI 0.93-10.67, p=0.057) was noted with the recessive genetic model. In agreement with that, a Kaplan-Meier analysis showed a significantly shorter time-to-discontinuation of MTX monotherapy for homozygous carriers of the T-allele (p=0.042).
  
  
  CONCLUSIONS
  These results demonstrate that the C677T polymorphism in the MTHFR gene is involved in MTX monotherapy discontinuation in a multicentre European patient cohort, confirming previous results.
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: María
authors: M
authors: Uribarri
authors: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors: Otsanda
authors: O
authors: Ruiz-Larrañaga
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: David
authors: D
authors: Arteta
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: Lorena
authors: L
authors: Hernández
authors: Department of Research and Development, Toscana Biomarkers S.r.l., Siena, Italy.
authors: Maria Claudia
authors: MC
authors: Alcaro
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: Antonio
authors: A
authors: Martínez
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: Sergio
authors: S
authors: Escorza-Treviño
authors: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors: Andone
authors: A
authors: Estonba
authors: Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Paola
authors: P
authors: Migliorini
authors: Department of Rheumatology and Immunology, University of Pécs, Medical Centre, Pécs, Hungary.
authors: László
authors: L
authors: Czirják
authors: Department of Research and Development, Progenika Biopharma S.A., Derio, Spain.
authors: Jokin
authors: J
authors: del Amo
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016009:Chi-Square Distribution; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006814:Hungary; D007558:Italy; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate