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 (7.5â15.0âmg 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: 1.26â8.79). 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: 1.13â2.81). 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chan ES, Cronstein BN . Molecular action of methotrexate in inflammatory diseases. Arthritis Res 2002; 4: 266â273.
Wang Y, Zhao R, Wang Y, Zhao R, Russell RG, Goldman ID . Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biophys Acta 2001; 1513: 49â54.
Trippett TM, Bertino JR . Therapeutic strategies targeting proteins that regulate folate and reduced folate transport. J Chemother 1999; 11: 3â10.
Drori S, Sprecher H, Shemer G, Jansen G, Goldman ID, Assaraf YG . Characterization of a human alternatively spliced truncated reduced folate carrier increasing folate accumulation in parental leukemia cells. Eur J Biochem 2000; 267: 690â702.
Tolner B, Roy K, Sirotnak FM . Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5â² end heterogeneity. Gene 1998; 211: 331â341.
Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2766â2774.
Dervieux T, Furst D, Lein DO, Capps R, Smith K, Caldwell J et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis 2005; 64: 1180â1185.
Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M . Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002; 100: 3832â3834.
Warren MD, Nichols AP, Bender RA . Membrane transport of methotrexate in human lymphoblastoid cells. Cancer Res 1978; 38: 668â671.
Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH . Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 2002; 108: 1â6.
Ding BC, Ding BC, Witt TL, Hukku B, Heng H, Zhang L et al. Association of deletions and translocation of the reduced folate carrier gene with profound loss of gene expression in methotrexate-resistant K562 human erythroleukemia cells. Biochem Pharmacol 2001; 61: 665â675.
Gorlick R, Goker E, Trippett T, Steinherz P, Elisseyeff Y, Mazumdar M et al. Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. Blood 1997; 89: 1013â1018.
Rothem L, Ifergan I, Kaufman Y, Priest DG, Jansen G, Assaraf YG . Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukaemia cell lines. Biochem J 2002; 367: 741â750.
Wong SC, Zhang L, Witt TL, Proefke SA, Bhushan A, Matherly LH . Impaired membrane transport in methotrexate-resistant CCRF-CEM cells involves early translation termination and increased turnover of a mutant reduced folate carrier. J Biol Chem 1999; 274: 10388â10394.
Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS et al. A polymorphism (80G>A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 2000; 70: 310â315.
Morin I, Devlin AM, Leclerc D, Sabbaghian N, Halsted GH, Finnell R et al. Evaluation of genetic veriants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Mol Genet Metab 2003; 79: 197â200.
Whetstine JR, Gifford AJ, Witt T, Liu XY, Flateley RM, Norris M et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterisation of a high frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clin Cancer Res 2001; 7: 3416â3422.
Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G et al. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 2004; 14: 733â739.
Rhee MS, Galivan J . Conversion of methotrexate to 7-hydroxymethotrexate and 7-hydroxymethotrexate polyglutamates in cultured rat hepatic cells. Cancer Res 1986; 46: 3793â3797.
Kremer JM, Galivan J, Streckfuss A, Kamen B . Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986; 29: 832â835.
Wolfe F, O'Dell JR, Kavanaugh A, Wilske K, Pincus T . Evaluating severity and status in rheumatoid arthritis. J Rheumatol 2001; 28: 1453â1462.
Pincus T, Summey JA, Soraci Jr SA, Wallston KA, Hummon NP . Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum 1983; 26: 1346â1353.
Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on outcome measures in rheumatoid arthritis clinical trials. Arthritis Rheum 1993; 36: 729â740.
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727â735.
Acknowledgements
The study was supported by Grant 2P05B11029 for years 2005â2008 from the Ministry of Education and Science (Warsaw, Poland).
Author information
Authors and Affiliations
Corresponding author
Additional information
Duality of interest:
None declared.
Rights and permissions
About this article
Cite this article
Drozdzik, M., Rudas, T., Pawlik, A. et al. Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J 7, 404â407 (2007). https://doi.org/10.1038/sj.tpj.6500438
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.tpj.6500438
Keywords
This article is cited by
-
The impact of folate pathway variants on the outcome of methotrexate therapy in rheumatoid arthritis patients
Clinical Rheumatology (2024)
-
AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients
The Pharmacogenomics Journal (2021)
-
Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a systematic review
The Pharmacogenomics Journal (2020)
-
MicroRNA-132, miR-146a, and miR-155 as potential biomarkers of methotrexate response in patients with rheumatoid arthritis
Clinical Rheumatology (2019)
-
Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis
Scientific Reports (2018)