title: Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?
abstract: BACKGROUND
  Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients' therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX.
  
  
  METHODS
  Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created.
  
  
  RESULTS
  Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1.
  
  
  CONCLUSIONS
  This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.
authors.affiliation: Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), 4585-116 Gandra PRD, Portugal. aurea.lima@iscsn.cespu.pt.|Grupo de Oncologia Molecular & Patologia Viral-Centro de Investigação do Instituto Português de Oncologia do Porto (CI-IPOP), 4200-072 Porto, Portugal. aurea.lima@iscsn.cespu.pt.|Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal. aurea.lima@iscsn.cespu.pt.
authors.forename: Aurea
authors.initials: A
authors.lastname: Lima
authors.affiliation: Faculdade de Medicina da Universidade do Porto (FMUP), 4200-319 Porto, Portugal. mbernardes09@gmail.com.|Departamento de Reumatologia do Centro Hospitalar de São João, 4200-319 Porto, Portugal. mbernardes09@gmail.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Bernardes
authors.affiliation: Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal. rita.pereir@hotmail.com.|Grupo de Patologia & Terapêutica Experimental do Centro de Investigação do Instituto Português de Oncologia do Porto (CI-IPOP), 4200-072 Porto, Portugal. rita.pereir@hotmail.com.
authors.forename: Rita
authors.initials: R
authors.lastname: Azevedo
authors.affiliation: Grupo de Oncologia Molecular & Patologia Viral-Centro de Investigação do Instituto Português de Oncologia do Porto (CI-IPOP), 4200-072 Porto, Portugal. rita.pereir@hotmail.com.|Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal. rita.pereir@hotmail.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), 4585-116 Gandra PRD, Portugal. vitor.seabra@iscsn.cespu.pt.
authors.forename: Vítor
authors.initials: V
authors.lastname: Seabra
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C427207:SLC22A11 protein, human; C421109:multidrug resistance-associated protein 1
keywords: ATP-binding cassette; clinical response; genetic risk index; methotrexate; polymorphisms; rheumatoid arthritis; solute carriers; transporters