Genetic biomarkers of MTX response:
MTHFR: Methylenetetrahydrofolate reductase (MTHFR) is probably the most widely studied gene in RA. This gene encodes an important enzyme that catalyzes various reactions in the MTX cellular pathways. Studies show that:
- Patients having MTHFR 1298AA and MTHFR 677CC genotype show better clinical improvement with MTX.
- MTHFR677TT carriers have more than 4-fold risk for nonresponse to MTX when compared to MTHFR677C carriers.
ATIC: ATIC is an important gene involved in the metabolism of MTX. Studies have shown that:
- ATIC 347CC genotype is associated with high MTX efficacy.
- ATIC 347GG genotype is associated with high risk of gastrointestinal adverse effects related to MTX.
- ATIC 347 GG+GC genotype is associated with lack of response to MTX and MTX related toxicity in Caucasian patients with RA.
MTX transporters: RFC-1 80G > A is a folate transport protein with high affinity to MTX.
- People with RFC1 80A allele (AA-GA) respond better to MTX than those with the RFC1 80 GG genotype.
- Patients with RFC-1 AA genotype respond better to MTX therapy than carriers of AG and GG genotypes.
- MTR / MTRR : MTR and MTRR enzymes participate in folate and adenosine metabolism. MTR AG and MTRR G allele have been found to show poor response of MTX in RA patients.
- Thymidilate synthase: Thymidilate synthase (TS) is a folate pathway enzyme that is inhibited by MTX polyglutamates (MTX is converted to MTX polyglutamates in the cell). Patients having ‐3R allele of the genetic variant in the enhancer region of thymidylate synthase which encodes TS (TYMS‐TSER‐2R/3R) have higher TYMS mRNA expression than those with ‐2R and require a higher MTX dosage.
MTX pharmacogenomics research challenges
- The genetic biomarkers of MTX discussed in this article lack a strong evidence base that supports its use in personalizing care.
- Although, the genetic biomarkers of MTX are good predictors of drug effectiveness, they still don’t fully explain the patient response to treatment.
- Various factors such as sex, ethnicity, RF status, duration of the disease and treatment, prescribed dose of MTX, MTX with or without the combination of other drugs and even the baseline disease activity of the participants in the pharmacogenomic studies might greatly influence the correlation of genetic polymorphisms and the MTX efficacy.