Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis

Pharmacogenetics. 2004 Nov;14(11):733-9. doi: 10.1097/00008571-200411000-00004.


We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / drug therapy
  • Base Sequence
  • Chromatography, High Pressure Liquid
  • DNA Primers
  • Humans
  • Membrane Transport Proteins / genetics*
  • Methotrexate / administration & dosage
  • Methotrexate / analogs & derivatives*
  • Methotrexate / blood*
  • Methotrexate / therapeutic use
  • Middle Aged
  • Polyglutamic Acid / analogs & derivatives*
  • Polyglutamic Acid / blood*
  • Polymorphism, Genetic*
  • Reduced Folate Carrier Protein
  • gamma-Glutamyl Hydrolase / blood*


  • DNA Primers
  • Membrane Transport Proteins
  • Reduced Folate Carrier Protein
  • SLC19A1 protein, human
  • Polyglutamic Acid
  • methotrexate polyglutamate
  • gamma-Glutamyl Hydrolase
  • Methotrexate