title: Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate.
abstract: OBJECTIVE
  To determine whether genetic polymorphisms within the folate pathway are associated with red blood cell (RBC) methotrexate (MTX) polyglutamate concentrations, RBC folate concentrations and MTX efficacy/toxicity.
  
  
  METHODS
  Disease activity in 200 rheumatoid arthritis patients on MTX was assessed by swollen and tender joint counts and Disease Activity Score 28. Genetic polymorphisms shown to have an effect on gene expression or protein function were examined.
  
  
  RESULTS
  RBC folate concentrations were significantly associated with MTHFR 677C>T (P=0.002), MTRR 66A>G (P<0.0001), MTHFD1 1958G>A (P=0.001) and SHMT 1420C>T (P=0.012), whereas no association of these polymorphisms with disease activity was observed. None of the polymorphisms tested predicted RBC MTX polyglutamate concentrations. There were weak associations between central nervous system adverse effects and AMPD1 34C>T (P=0.04) and between gastrointestinal adverse effects and MTHFD1 1958G>A (P=0.03) and ABCC2 IVS23+56T>C (P=0.045). There was a stronger association between any adverse effect and ABCG2 914C>A (P=0.004).
  
  
  CONCLUSIONS
  Although RBC folate concentrations are associated with genetic polymorphisms within the folate pathway, these variants do not predict disease activity. To accurately evaluate whether any polymorphisms are reliable predictors of MTX efficacy or toxicity, large prospective clinical trials are required. Furthermore, application of a genome-wide association strategy is likely to uncover novel predictors of MTX response.
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.forename: Peter T
authors.initials: PT
authors.lastname: Chapman
authors.forename: John L
authors.initials: JL
authors.lastname: O'Donnell
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Jill
authors.initials: J
authors.lastname: James
authors.forename: Christopher
authors.initials: C
authors.lastname: Frampton
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
mesh_terms: D000659:AMP Deaminase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D005287:Ferredoxin-NADP Reductase; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008727:Methotrexate / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D011099:Polyglutamic Acid / Q000031:analogs & derivatives; D011110:Polymorphism, Genetic
chemical_list: C000715087:ABCC2 protein, human; D000089762:Multidrug Resistance-Associated Protein 2; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase; D000659:AMP Deaminase; D008727:Methotrexate