FRI0041 Associations between tyms polymorphisms and responsiveness to or toxicity of methotrexate in rheumatoid arthritis

Abstract

Background: Thymidylate synthase (TYMS) is a key protein in the De novo synthesis of pyrimidines, and is essential for DNA replication and cell proliferation. MTX is polyglutamylated to form MTX polyglutamates after entering cells, and directly inhibits TYMS. TYMS is an important target for MTX, and over-expression of the TYMS gene is associated with resistance to TYMS-targeted drugs. Objective(s): The aim of this study was to investigate whether the thymidylate synthase (TYMS) 2R/3R and 6 bp I/D polymorphisms can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Method(s): We conducted a meta-analysis of studies on the association between the TYMS 2R/3R and 6 bp I/D polymorphisms and non-responsiveness to or toxicity of MTX in RA patients. Result(s): A total of 11 studies involving 1613 patients were considered. Metaanalysis showed no association between the TYMS 2R/3R 3R allele and nonresponsiveness to MTX therapy (OR=1.087 CI=0.682-1.731, p=0.726). The meta-analysis indicated that there was no association between the TYMS 6 bp I/ D D allele and non-responsiveness to MTX therapy (OR=0.688, 95% CI=0.281- 1.683, p=0.413). Meta-analysis revealed no association between the overall toxicity of MTX treatment in RA and the TYMS 2R/3R 3R allele. However, meta-analysis revealed that MTX toxicity was associated with the TYMS 2R/3R polymorphism in RA patients when a co-dominant model (3 R2R vs. 3 R3R +2R2R) was used, indicating that heterozygotes (3 R2R) for the polymorphism had a higher risk of developing MTX toxicity than homozygotes (3 R3R+2R2R). Stratification by ethnicity indicated an association between the TYMS 2R/3R 3R allele and non-responsiveness to MTX in Caucasians, but not in non-Caucasians. In contrast, meta-analysis revealed no association between the overall toxicity of MTX and the TYMS 6 bp I/D D allele. Conclusion(s): This meta-analysis demonstrates that the TYMS 2R/3R and 6 bp I/D polymorphisms may not be associated with non-responsiveness to MTX therapy, but that the TYMS 2R/3R polymorphism may be associated with MTX toxicity in RA, particularly in Caucasians.