Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatment in rheumatoid arthritis patients: evidence from a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to evaluate the association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism A1298C and methotrexate (MTX) outcome in rheumatoid arthritis (RA) patients.

METHODS: We conducted a meta-analysis of the relevant published literature through to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models.

RESULTS: A total of 1325 cases (10 studies) of MTX efficacy and 2777 cases (18 studies) of MTX toxicity in RA patients were analyzed. Pooled results showed that MTHFR gene A1298C polymorphism was not significantly related to MTX toxicity or efficacy in RA patients. However, subgroup analysis indicated a significant association between MTHFR gene A1298C polymorphism and decreased MTX efficacy in the South Asian population (CCvs. CA + AA: OR = 0.45, 95% CI = 0.23-0.89, P = 0.021). Also, MTHFR gene A1298C polymorphism in the partial folate supplementation group showed a relationship with decreased MTX efficacy (CCvs. CA + AA: OR = 0.43, 95% CI = 0.20-0.92, P = 0.029) and toxicity (CCvs. CA + AA: OR = 0.40, 95% CI = 0.17-0.96, P = 0.04; CCvs. AA: OR = 0.38, 95% CI = 0.16-0.94, P = 0.035).

CONCLUSIONS: Overall, our meta-analysis suggested no significant effect of MTHFR gene A1298C polymorphism on MTX outcome in RA patients. However, due to several limitations of our meta-analysis, the results should be interpreted cautiously and require further confirmation using high-quality studies.