title: Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis: A systematic review and meta-analysis.
abstract: BACKGROUND
  Methotrexate (MTX) is widely used and considered a first-line disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, 10% to 30% of patients discontinue therapy within a year of starting the treatment, usually because of undesirable side effects. Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX toxicity in RA patients, although inconsistent results have been reported.
  
  
  METHODS
  We searched EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the toxicity of MTX monotherapy in RA patients. The meta-analysis was stratified by whether genetic variants associated with MTX toxicity.
  
  
  RESULTS
  A total of 42 publications that included 28 genes with 88 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the SR, and 31 studies were included in 7 meta-analyses. The meta-analysis showed a significant association between the toxicity of MTX and the RFC-1 80G > A (rs1051266) polymorphism in the European RA patients.
  
  
  CONCLUSIONS
  RFC-1 80G > A (rs1051266) polymorphism was associated with MTX toxicity, and larger and more stringent study designs may provide more accurate results for the effect of these SNPs on the MTX toxicity.
authors.affiliation: Institute of Clinical Pharmacology, Beijing Anzhen Hospital, Capital Medical University Institute of Clinical Medicine, China-Japan Friendship Hospital Beijing University of Chinese Medicine Department of Rheumatology, China-Japan Friendship Hospital, Beijing Department of Gastroenterology, People's Hospital of Yichun, Jiangxi Yichun Department of Rheumatology, Yili Kazak Autonomous Prefecture Hospital of Traditional Chinese Medicine, Xinjiang Yining, China Department of Dermatology and Skin Science, University of British Columbia Molecular Medicine Lab and Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Qiu
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: Lin
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Shu
authors.forename: Huizheng
authors.initials: H
authors.lastname: Fan
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Tu
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Cheng
authors.initials: C
authors.lastname: Xiao
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015415:Biomarkers; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D051818:Replication Protein C / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018501:Antirheumatic Agents; D015415:Biomarkers; D009097:Multienzyme Complexes; C081632:RFC1 protein, human; C113120:inosine monophosphate synthase; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D051818:Replication Protein C; D008727:Methotrexate