Skip to main page content (V体育ios版)
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

Multicenter Study
. 2009 Feb;160(2):438-41.
doi: 10.1111/j.1365-2133.2008.08898.x. Epub 2008 Oct 25.

Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms

R B Warren  1 , R L Smith, E Campalani, S Eyre, C H Smith, J N W N Barker, J Worthington, C E M Griffiths
Affiliations
Multicenter Study

Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms

R B Warren (V体育官网) et al. Br J Dermatol. 2009 Feb.

Abstract

Background: The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug VSports手机版. .

Objectives: To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis V体育安卓版. .

Methods: DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0. 8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data V体育ios版. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom). .

Results: There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated VSports最新版本. .

Conclusions: Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis V体育平台登录. .

PubMed Disclaimer

Figures

Fig 1
Fig 1
Illustration of some of the key enzymes involved in the metabolism of methotrexate (MTX). MTX is transported into the cell via the solute carrier family 19, member 1 (SLC19A1). It can be actively transported out of the cell by the ATP-binding cassette transporters including ATP-binding cassette, subfamily C (CFTR/MRP), member 1–4 (ABCC1-C4) and ATP-binding cassette, subfamily G, member 2 (ABCG2). Within the cell it undergoes polyglutamation (activation) under the enzymic control of folylpolyglutamate synthase (FPGS). This is a dynamic process where glutamate residues can be removed by gamma-glutamyl hydrolase (GGH). In the polyglutamated form MTX inhibits aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), which probably accounts for some of its anti-inflammatory effects via an intracellular rise in adenosine. Inhibition of the folate pathway may not be as important to its mechanism of action in psoriasis, but this pathway includes the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) which has been subject to a number of MTX pharmacogenetic studies in the past. MTHFR catalyses the conversion of 5,10-methylenetetrahydrofolate 5,10-CH2-THF to 5-methyltetrahydofolate (5-CH3-THF), which is a cosubstrate for homocysteine remethylation. The polyglutamated form of MTX also inhibits thymidylate synthase (TYMS), which converts deoxyuridylate (dUMP) to deoxythymidylate (dTMP) in the de novo pyrimidine biosynthetic pathway. Genes chosen for this investigation are highlighted in red.
See this image and copyright information in PMC

"V体育安卓版" References

    1. van Ede AE, Laan RF, Blom HJ, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum. 2001;44:2525–30. - PubMed (VSports)
    1. Urano W, Taniguchi A, Yamanaka H, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 2002;12:183–90. - PubMed
    1. Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127:1860–7. - PubMed (V体育安卓版)
    1. Berkun Y, Levartovsky D, Rubinow A, et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis. 2004;63:1227–31. - PMC - PubMed
    1. Wessels JA, de Vries-Bouwstra JK, Heijmans BT, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54:1087–95. - PubMed

MeSH terms