Association of folylpolyglutamate synthase polymorphisms with methotrexate response and toxicity in rheumatoid arthritis: a meta-analysis

Abstract

This meta-analysis evaluated the association between FPGS gene polymorphisms (rs10106 (1994A > G) and rs1544105 (2572 C > T)) and methotrexate (MTX) efficacy and toxicity in rheumatoid arthritis (RA). Studies published up to October 2025 were identified through PubMed, Embase, Web of Science, Scopus, and manual searches. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated under various genetic models. Subgroup and sensitivity analyses were conducted, and publication bias was assessed using Egger’s test. Ten studies involving 2345 RA patients receiving MTX were included in this meta-analysis. The FPGS rs10106 G allele was significantly associated with enhanced MTX efficacy in the dominant model (OR = 1.22, 95% CI: 1.05–1.41, p = 0.009) and homozygous model, although the allelic model showed only borderline significance (p = 0.052). In contrast, rs10106 was consistently associated with increased toxicity across all genetic models (all p ≤ 0.001). For rs1544105, the T allele showed robust and highly significant associations with both improved efficacy (dominant model OR = 1.66, 95% CI: 1.45–1.89, p < 0.001) and higher toxicity risk across all analyzed models (all p < 0.001). Significant effects were observed mainly in Asian and European populations, with no associations in US/Other groups. Results were robust with no evidence of publication bias. FPGS rs10106 and rs1544105 polymorphisms significantly influence MTX response and toxicity in RA, with ethnic variability, supporting their potential use in individualized MTX therapy.