alexa Genetic Determinants Of Methotrexate Toxicity In Tunisian Patients With Rheumatoid Arthritis: A Study Of Polymorphisms In Key Methotrexate Pathway Genes
ISSN: 2161-0495

Journal of Clinical Toxicology
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9th Euro-Global Summit on Toxicology and Applied Pharmacology
June 22-24, 2017 Paris, France

Abdellatif Maalej , Souhir Chaabane, Sameh Marzouk, Rim Akrout, Mariem Ben Hamad, Yosser Achour, Ahmed Rebai, Leila Keskes, Hela Fourati and Zouhir Bahloul
Laboratory of Human Molecular Genetics, Faculty of Medicine, Sfax, Tunisia
University Hospital Hedi Chaker, Sfax, Tunisia
Department of Bioinformatics, Center of Biotechnology, Sfax, Tunisia.
Posters & Accepted Abstracts: J Clin Toxicol
DOI: 10.4172/2161-0495-C1-025
Abstract
Introduction: 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 present in 40% of the patients. Aim: The purpose of this study was to investigate the influence of genetic polymorphisms in genes involved in the folate metabolic pathway (MTHFR, DHFR), methionine pathway (MTR, MTRR), pyrimidine synthesis (TYMS) and the MTX transport pathway (RFC1, ABCB1, ABCC2) on the occurrence of MTX-related toxicity (overall and gastrointestinal) and to identify pharmacogenetic markers of MTX toxicity in a group of Tunisian RA patients. Methods: A total of 182 patients with rheumatoid arthritis, under MTX treatment were investigated in this study. Clinicopathological data were collected and ADRs were recorded. A genotyping approach was performed using PCR, PCRRFLP and TaqMan allelic discrimination method to determine the studied polymorphisms. Association analyses with regard to MTX-related toxicity were evaluated using χ2 test, genotype relative risk (GRR) and the toxicogenetic risk index (TRI). Results: Statistical analysis revealed that RFC1 80G/G genotype had increased risk of gastrointestinal toxicity (p=0.032), as well as the T/T genotype of MTHFR C677T polymorphism was associated with both overall and gastrointestinal toxicity (p=0.0007), while TYMS 2R→3R polymorphism had a protective effect against overall MTX toxicity (p=0.031). However, we did not find any association of the MTHFR A1298C, DHFR 19–base pair deletion allele, MTR A2756G, MTRR A66G, ABCB1 C3435T and ABCC2 G1249A polymorphisms with MTX toxicity. Conclusion: This study demonstrated that genotyping of MTHFR C677T and RFC1 G80A may be a possible predictor to identify patients with increased risk for developing overall and gastrointestinal toxicity related to MTX treatment in Tunisian patients.
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