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Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid

Michael H Weisman1, Daniel E Furst, Grace S Park

  • 1Cedars-Sinai Medical Center, Los Angeles, California, USA.

Arthritis and Rheumatism
|February 1, 2006
PubMed
Abstract

Insights

Risk genotypes in folate-dependent enzymes predict methotrexate toxicity in rheumatoid arthritis patients. A composite index effectively identifies individuals prone to adverse effects, aiding personalized treatment strategies.

Area of Science:

  • Pharmacogenomics
  • Rheumatology
  • Clinical Chemistry

Background:

  • Methotrexate (MTX) is a cornerstone antifolate therapy for rheumatoid arthritis (RA).
  • MTX therapy is frequently limited by dose-dependent toxicities.
  • Genetic variations in folate metabolism pathways may influence MTX tolerability.

Purpose of the Study:

  • To investigate the association between genetic polymorphisms in folate-dependent enzymes and MTX-induced toxicity in RA patients.
  • To develop and validate a toxicogenetic index for predicting MTX side effects.

Main Methods:

  • A multicenter, cross-sectional study involving 214 RA patients on MTX therapy.
  • Genotyping for low-penetrance risk alleles in MTHFR, TSER, ATIC, and SHMT1.
  • Calculation of a composite toxicogenetic index and logistic regression analysis to assess associations with reported side effects.

Main Results:

  • 31% of patients experienced adverse events, including gastrointestinal issues, headache, lethargy, and alopecia.
  • Specific genotypes (MTHFR 677TT, SHMT1 1420CC) were linked to central nervous system side effects.
  • ATIC 347GG and TSER*2/*2 were associated with gastrointestinal and alopecia side effects, respectively.
  • A higher toxicogenetic index (0-3) correlated significantly with an increased likelihood of experiencing MTX side effects (OR ~7 for index 3 vs. 0).

Conclusions:

  • Cumulative risk genotypes in folate-dependent enzymes can be effectively combined into a toxicogenetic index.
  • This index shows promise for profiling RA patients at higher risk for MTX-related toxicities.
  • Personalized risk assessment using genetic profiling may optimize MTX treatment strategies.

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