Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis

Methotrexate (MTX), widely used in the treatment of rheumatoid arthritis (RA), inhibits dihydrofolate reductase (DHFR) and folate-dependent enzymes. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) are key enzymes in the folate metabolism and both have been shown to be polymorphic affecting the enzyme activity. To clarify the association between these genetic variations and MTX-related toxicity and efficacy in the treatment of RA, a total of 167 Japanese individuals with RA, including 52 and 63 patients treated with low-dose MTX with or without adverse effects, respectively, and 52 patients without MTX administration were analyzed. Among the 93 patients treated with MTX for >2 months, significantly more patients homozygous for the triple-repeat allele of the polymorphism in the promoter region of the TYMS gene required higher dose of MTX compared to those having at least a double-repeat allele (P=0.033). The incidence of ≥50% improvement in the serum CRP level was significantly higher in patients homozygous for the deletion allele of the polymorphism in the 3'-untranslated region (UTR) of the TYMS gene (P=0.0383). The allele frequency of the insertion/deletion polymorphism in the TYMS 3'UTR in Japanese was significantly different from that in Caucasians (P<0.0001), as was the tandem-repeat polymorphism in its promoter region. On the other hand, MTHFR C677T and A1298C polymorphisms showed no association with MTX-related toxicity or efficacy. Our results suggest that the genotyping for the TYMS polymorphisms may become a useful indicator in determining the appropriate dose of MTX in patients with RA.