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European Journal of Drug Metabolism and Pharmacokinetics
Erschienen in: European Journal of Drug Metabolism and Pharmacokinetics 4/2016

01.08.2016 | Original Paper

Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway

verfasst von: Souhir Chaabane, Sameh Marzouk, Rim Akrout, Mariem Ben Hamad, Yosser Achour, Ahmed Rebai, Leila Keskes, Hela Fourati, Zouhir Bahloul, Abdellatif Maalej

Erschienen in: European Journal of Drug Metabolism and Pharmacokinetics | Ausgabe 4/2016

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Abstract

Background and Objective

Methotrexate (MTX) is a disease-modifying anti-rheumatic drug used in the treatment of rheumatoid arthritis (RA). It is the first line drug in the treatment of this disease. However, MTX-related adverse drug reactions (ADRs) are seen in 40 % of the patients. The aim of this study was to determine the impact of six genetic polymorphisms located in five genes encoding proteins involved in the MTX metabolic pathway in Tunisian RA patients and evaluate its association with MTX toxicity.

Methods

Genotyping of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), dihydrofolate reductase (DHFR 19–base pair deletion allele), thymidylate synthase (TYMS 2R/3R), methionine synthase (MTR A2756G) and methionine synthase reductase (MTRR A66G) was performed using PCR and PCR–RFLP method in 141 RA patients treated with MTX. Demographic and clinical characteristics were obtained and ADRs were recorded. Association analyses with regard to MTX toxicity were performed using the χ 2 test, the toxicogenetic risk index (TRI) and the Mann–Whitney U-test.

Results

The analysis highlighted a significant association of the T/T genotype of MTHFR C677T polymorphism with increased MTX toxicity. However, the MTHFR A1298C, DHFR 19-base pair deletion allele, MTR A2756G and MTRR A66G polymorphisms were not associated with increased MTX toxicity. The TYMS 2R/3R polymorphism had a protective effect against MTX toxicity.

Conclusion

The results demonstrated that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in Tunisian RA patients. In contrast, the TYMS 2R/3R polymorphism is associated with a protective effect against overall MTX toxicity.
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Metadaten
Titel
Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway
verfasst von
Souhir Chaabane
Sameh Marzouk
Rim Akrout
Mariem Ben Hamad
Yosser Achour
Ahmed Rebai
Leila Keskes
Hela Fourati
Zouhir Bahloul
Abdellatif Maalej
Publikationsdatum
01.08.2016
Verlag
Springer International Publishing
Erschienen in
European Journal of Drug Metabolism and Pharmacokinetics / Ausgabe 4/2016
Print ISSN: 0378-7966
Elektronische ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-015-0288-z

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