The C677T mutation in the methylenetetrahydrofolate reductase gene - A genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients

Objective. To study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid a rthritis (RA). Methods. Genotype analysis of the MTHFR gene was done in 236 patients who s tarted MTX treatment with (n = 157) or without (n = 79) folic or folinic ac id supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevat ed liver enzyme levels during the study. Multivariate logistic regression a nalysis was used to study the relationship between the presence of the MTHF R C677T mutation and toxicity outcomes of MTX treatment. Results. Forty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotype s was associated with an increased risk of discontinuing MTX treatment beca use of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3. 70), mainly due to an increased risk of elevated liver enzyme levels (relat ive risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters wer e not significantly different between the patients with and those without t he mutation. Conclusion. The C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patien ts with RA. We postulate that the incidence of clinically important elevati on of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.