The effect of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene has been evaluated. Several polymorphisms have been identified, although two single-nucleotide polymorphisms (SNPs), C677T and A1298C, have been commonly linked to adverse drug events. The C677T is a common polymorphism, with mutant homozygotes representing around 8% of the Caucasian population. This polymorphism leads to an alanine ! valine substitution that makes the enzyme more thermolabile; this variant has a 30% reduced enzymatic activity compared with the wild-type (29). Van Ede et al. (34) studied the C677T polymorphism with regard to toxicity and efficacy of MTX in 236 RA patients. They found that 48% of the patients carried at least one T allele and that the presence of the C677CT or C677TT genotype increased the risk of stopping MTX due to adverse events (RR 2.01, 95% CI 1.09-3.7), especially increased liver transaminases (RR 2.38, 95% CI 1.06-5.34). No difference in MTX efficacy was seen between the groups. In a Japanese cohort of 106 RA patients, Urano et al. (35) studied two polymorphisms of MTHFR, the C677T polymorphism and the A1298C polymorphism. The latter polymorphism results in a glutamine ! alanine substitution and reduced enzyme activity. In this cohort, MTX toxicity was more frequent in patients with the C677T allele, compared with those without the T allele (27% vs. 8.6%, RR 1.25, p < 0.05). No correlation was observed between this polymorphism and treatment efficacy. In 80 patients, the A1298C polymorphism was also studied. Patients with the C allele required significantly lower doses of MTX than patients without the allele (RR 2.18, 95% CI 1.17-4.06, p < 0.05), and there was a trend towards improved efficacy in patients with the C allele, with greater improvements in the ESR and CRP. There was, however, a higher baseline ESR in the C/ C group. No association was observed between A1298C polymorphism and toxicity. They concluded that the C677T polymorphism leads to increased toxicity, whereas A1298C improved efficacy of MTX. A second study, however, found no association between MTHFR C677T or A1298C genotypes and outcome of the MTX treatment in a Japanese cohort (36).

Clearly there are other potential candidate genes that may affect MTX efficacy and toxicity, including dihydrofolate reductase, thymidylate synthase, and folylpolyglutamate synthase (which mediates the polyglutamation of MTX). To date, only a single study (36) has examined the effect of polymorphisms in the thymidylate synthase gene (TYMS) and outcome of MTX treatment. Patients who were homozygous for the triple-repeat allele in the promoter region of the TYMS gene required higher doses of MTX than those carrying the double-repeat allele (p = 0.033), although all patients were on low doses of MTX. In addition patients who were homozygous for the deletion allele of the polymorphism in the 3'-untranslated region of the TYMS gene had a higher rate of improvement (measured by a 50% fall in the CRP level) than patients without this polymorphism (p = 0.383). Clearly these studies require replication, but it is likely that polymorphisms in these and other enzymes in the MTX pathway will be of importance in predicting efficacy and/or toxicity to MTX.

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