Souhir Chaabane1, Sameh Marzouk2, Rim Akrout3, Mariem Ben Hamad4, Yosser Achour4, Ahmed Rebai5, Leila Keskes4, Hela Fourati3, Zouhir Bahloul2, Abdellatif Maalej6. 1. Laboratory of Human Molecular Genetics, Faculty of Medicine, Avenue Majida Boulila, 3029, Sfax, Tunisia. chaabane.souhir@yahoo.fr. 2. Department of Internal Medicine, University Hospital Hedi Chaker, Sfax, Tunisia. 3. Department of Rheumatology, University Hospital Hedi Chaker, Sfax, Tunisia. 4. Laboratory of Human Molecular Genetics, Faculty of Medicine, Avenue Majida Boulila, 3029, Sfax, Tunisia. 5. Department of Bioinformatics, Center of Biotechnology, Sfax, Tunisia. 6. Laboratory of Human Molecular Genetics, Faculty of Medicine, Avenue Majida Boulila, 3029, Sfax, Tunisia. abdellatifmaalej@yahoo.fr.
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.
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 RApatients and evaluate its association with MTXtoxicity. METHODS: Genotyping of 5,10 methylenetetrahydrofolate reductase (MTHFRC677T and A1298C), dihydrofolate reductase (DHFR 19-base pair deletion allele), thymidylate synthase (TYMS 2R/3R), methionine synthase (MTR A2756G) and methionine synthase reductase (MTRRA66G) was performed using PCR and PCR-RFLP method in 141 RApatients treated with MTX. Demographic and clinical characteristics were obtained and ADRs were recorded. Association analyses with regard to MTXtoxicity 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 MTHFRC677T polymorphism with increased MTXtoxicity. However, the MTHFRA1298C, DHFR 19-base pair deletion allele, MTR A2756G and MTRRA66G polymorphisms were not associated with increased MTXtoxicity. The TYMS 2R/3R polymorphism had a protective effect against MTXtoxicity. CONCLUSION: The results demonstrated that the C677T polymorphism in the MTHFR gene is associated with MTXtoxicity in Tunisian RApatients. In contrast, the TYMS 2R/3R polymorphism is associated with a protective effect against overall MTXtoxicity.
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Authors: Mirna Gisel González-Mercado; Fernando Rivas; M Patricia Gallegos-Arreola; M Cristina Morán-Moguel; Mario Salazar-Páramo; Laura González-López; J Iván Gámez-Nava; J Francisco Muñoz-Valle; Ricardo Medina-Coss Y León; Anahí González-Mercado; Mario A Aceves; Nory O Dávalos; Agustín Macías-Chumacera; Ingrid P Dávalos Journal: Genet Test Mol Biomarkers Date: 2017-10-10