title: Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms.
abstract: OBJECTIVE
  Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients.
  
  
  METHODS
  Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables.
  
  
  RESULTS
  Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response.
  
  
  CONCLUSIONS
  Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.
authors: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal ; Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal ; Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors: Aurea
authors: A
authors: Lima
authors: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.
authors: Joaquim
authors: J
authors: Monteiro
authors: Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal ; Rheumatology Department, São João Hospital Center, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors: Miguel
authors: M
authors: Bernardes
authors: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal ; Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal ; Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
authors: Hugo
authors: H
authors: Sousa
authors: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal ; Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors: Rita
authors: R
authors: Azevedo
authors: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences (ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal.
authors: Vitor
authors: V
authors: Seabra
authors: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal ; Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal ; Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal ; Research Department-Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação 6657, 4200-177 Porto, Portugal.
authors: Rui
authors: R
authors: Medeiros
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; 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*; D011110:Polymorphism, Genetic; D011174:Portugal; D012307:Risk Factors
chemical_list: D018501:Antirheumatic Agents; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D008727:Methotrexate