Two FPGS gene polymorphisms (rs10106 and rs1544105) significantly influence both methotrexate treatment effectiveness and toxicity risk in rheumatoid arthritis patients, with effects varying by ethnicity.
- FPGS rs1544105 T allele linked to 66% higher odds of better methotrexate response but also increased toxicity risk
- FPGS rs10106 G allele associated with 22% improved efficacy and consistently higher toxicity across all genetic models
- Effects observed mainly in Asian and European populations, not in US/Other groups
How this compares to prior research
Previous research has explored various genetic factors affecting methotrexate response in rheumatoid arthritis, but individual studies on FPGS polymorphisms have shown inconsistent results. This meta-analysis pooled data from multiple studies to provide more definitive evidence about the role of FPGS genetic variants. The findings clarify that specific FPGS polymorphisms consistently influence both treatment efficacy and toxicity, addressing previous uncertainties in the literature.
Rheumatoid arthritis prevalence among adults, global estimates, 1990–1999
Key findings
- Meta-analysis of 10 studies involving 2,345 rheumatoid arthritis patients receiving methotrexate identified significant genetic associations
- FPGS rs1544105 T allele showed strongest association with improved efficacy (OR 1.66) and toxicity risk across all genetic models
- FPGS rs10106 G allele linked to enhanced efficacy in dominant model (OR 1.22) and increased toxicity across all models
What this means in practice
- Ask your rheumatologist about FPGS genetic testing before starting methotrexate to predict treatment response and toxicity risk
- Consider that your ethnic background may influence how these genetic variants affect your methotrexate treatment outcomes
- Monitor closely for side effects if you carry FPGS variants associated with higher toxicity risk
Frequently asked questions
What is FPGS and why does it matter for methotrexate treatment?
FPGS (folylpolyglutamate synthase) is a gene that affects how the body processes methotrexate. Genetic variants in FPGS can predict whether methotrexate will work well or cause side effects in rheumatoid arthritis patients.
Which ethnic groups show these genetic associations?
The associations between FPGS variants and methotrexate response were significant in Asian and European populations but not observed in US/Other population groups.
Can genetic testing help personalize methotrexate therapy?
These findings support the potential use of FPGS genetic testing to individualize methotrexate therapy, helping predict both treatment effectiveness and toxicity risk before starting medication.
Key terms explained
Folylpolyglutamate synthase (FPGS)
An enzyme that modifies methotrexate inside cells, affecting how well the drug works and its side effects
Polymorphism
A variation in DNA sequence that differs between individuals and can affect drug response
Odds ratio (OR)
A statistical measure comparing the likelihood of an outcome; OR above 1.0 means increased odds
Source: Association of folylpolyglutamate synthase polymorphisms with methotrexate response and toxicity in rheumatoid arthritis: a meta-analysis. · DOI: pii: 11. doi: 10.1038/s41397-026-00404-6