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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.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Pomeranian Medical University, Szczecin, Poland.

    , , , ,

    Source

    The pharmacogenomics journal 7:6 2007 Dec pg 404-7

    MeSH

    Adult
    Aged
    Alanine Transaminase
    Antirheumatic Agents
    Arthritis, Rheumatoid
    Drug Therapy, Combination
    Female
    Folic Acid Antagonists
    Gene Frequency
    Genotype
    Humans
    Male
    Membrane Transport Proteins
    Methotrexate
    Methylprednisolone
    Middle Aged
    Odds Ratio
    Patient Selection
    Phenotype
    Polymorphism, Single Nucleotide
    Reduced Folate Carrier Protein
    Transaminases
    Treatment Outcome

    Pub Type(s)

    Clinical Trial
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17325736

    Citation

    Drozdzik, M, et al. "Reduced Folate Carrier-1 80G>A Polymorphism Affects Methotrexate Treatment Outcome in Rheumatoid Arthritis." The Pharmacogenomics Journal, vol. 7, no. 6, 2007, pp. 404-7.
    Drozdzik M, Rudas T, Pawlik A, et al. Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J. 2007;7(6):404-7.
    Drozdzik, M., Rudas, T., Pawlik, A., Gornik, W., Kurzawski, M., & Herczynska, M. (2007). Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. The Pharmacogenomics Journal, 7(6), pp. 404-7.
    Drozdzik M, et al. Reduced Folate Carrier-1 80G>A Polymorphism Affects Methotrexate Treatment Outcome in Rheumatoid Arthritis. Pharmacogenomics J. 2007;7(6):404-7. PubMed PMID: 17325736.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. AU - Drozdzik,M, AU - Rudas,T, AU - Pawlik,A, AU - Gornik,W, AU - Kurzawski,M, AU - Herczynska,M, Y1 - 2007/02/27/ PY - 2007/2/28/pubmed PY - 2008/1/9/medline PY - 2007/2/28/entrez SP - 404 EP - 7 JF - The pharmacogenomics journal JO - Pharmacogenomics J. VL - 7 IS - 6 N2 - 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. SN - 1470-269X UR - https://www.unboundmedicine.com/medline/citation/17325736/Reduced_folate_carrier_1_80G&gt L2 - http://dx.doi.org/10.1038/sj.tpj.6500438 DB - PRIME DP - Unbound Medicine ER -