Association Between MTRR 66 A/G and MTR 2756 A/G Polymorphisms and Response to Methotrexate in Rheumatoid Arthritis. A Meta-analysis

This study aimed to investigate the association between methotrexate (MTX) response in rheumatoid arthritis and the polymorphisms methionine synthase reductase (MTRR) 66 A/G and methionine synthase (MTR) 2756 A/G. Relevant studies were identified through searches in MEDLINE, EMBASE, Web of Science, and Cochrane databases. A meta-analysis was conducted to evaluate the relationship between MTX response and the MTRR 66 A/G and MTR 2756 A/G polymorphisms. Eight studies that examined MTRR 66 A/G (with 688 responders and 541 nonresponders) and MTR 2756 A/G (518 responders and 261 nonresponders) were included. The meta-analysis found no significant association between MTX responsiveness and the MTRR 66 GG + GA genotype (odds ratio [OR] = 1.289, 95% confidence interval [CI] = 0.991–1.676, p = 0.059). However, stratified analysis revealed a significant association in studies with larger sample sizes (n ≥ 150) (OR = 1.343, 95% CI = 1.015–1.776, p = 0.039), but not in smaller studies (n < 150) (OR = 0.952, 95% CI = 0.444–2.039, p = 0.899). No association was found with treatment response based on follow-up duration. The MTR 2756 GG + GA genotype also showed no significant association with MTX responsiveness (OR = 1.053, 95% CI = 0.765–1.450, p = 0.751). Subgroup analyses by ethnicity, sample size, and follow-up period revealed no additional associations with treatment response. The limited number of studies (n = 4) for the MTR 2756 A/G polymorphism was included in the meta-analysis for the MTR 2756 A/G polymorphism, which has the potential for reduced statistical power as a consequence. This meta-analysis suggests that the MTRR 66 A/G GG + GA genotype is associated with a better response to MTX treatment in rheumatoid arthritis, whereas the MTR 2756 A/G polymorphism does not significantly impact treatment response. However, the significant association between MTRR 66 A/G and MTX response was observed only in the subgroup of larger studies, which indicates that the overall strength of evidence might be weak.