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

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. 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 chi (2) test, the toxicogenetic risk index (TRI) and the Mann-Whitney U-test. 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. 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.