title: Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis.
abstract: The folate antagonist methotrexate (MTX) is a drug currently used in the treatment of rheumatoid arthritis (RA). MTX enters the cells through the reduced folate carrier (RFC-1) and is activated to polyglutamates. Previous studies have shown that RFC-1 expression may influence the efficacy of therapy with MTX. The studies suggest that G80A polymorphism in RFC-1 is associated with altered folate/antifolate levels and the subjects carrying homozygous mutant 80AA genotype tend to have higher plasma folate and MTX concentrations and higher erythrocyte polyglutamate levels compared with those with the wild type or heterozygous genotype. It is possible that this polymorphism might influence MTX treatment outcome in patients with RA. In the present study, we examined the association between RFC-1 G80A polymorphism and treatment outcome in patients with RA administered MTX. The study was carried out on 174 patients diagnosed with RA treated with MTX (7.5-15.0 mg weekly) plus low doses of methylprednisone. The RFC-1 80G>A polymorphism (resulting in a histidine-to-arginine substitution at codon 27 of RFC-1) was detected using a polymerase chain reaction-restriction fragment length polymorphism method. The probability of remission of RA symptoms was 3.32-fold higher in carriers of 80AA genotype as compared with patients with 80GG genotype (P=0.021, OR=3.32, 95% CI: 1.26-8.79). The frequency of A allele among MTX responders was 62.1, compared to 47.8% in a group of poor MTX responders (P=0.013, OR=1.78, 95% CI: 1.13-2.81). Moreover, the increase of aminotransferase activity was noted more frequently in carriers of 80AA genotype. The present data suggest that evaluation of RFC-1 gene 80G>A polymorphism may be a useful tool to optimize MTX therapy in patients with RA.
authors.affiliation: Department of Pharmacology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Drozdzik
authors.forename: T
authors.initials: T
authors.lastname: Rudas
authors.forename: A
authors.initials: A
authors.lastname: Pawlik
authors.forename: W
authors.initials: W
authors.lastname: Gornik
authors.forename: M
authors.initials: M
authors.lastname: Kurzawski
authors.forename: M
authors.initials: M
authors.lastname: Herczynska
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D016017:Odds Ratio; D018579:Patient Selection; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein; D000637:Transaminases / Q000097:blood; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D000637:Transaminases; D000410:Alanine Transaminase; C022636:serine-glyoxylate aminotransferase; D008775:Methylprednisolone; D008727:Methotrexate