title: Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.
abstract: 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.
authors.affiliation: Prometheus Laboratories, San Diego, California, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dervieux
authors.forename: Joel
authors.initials: J
authors.lastname: Kremer
authors.forename: Diana Orentas
authors.initials: DO
authors.lastname: Lein
authors.forename: Robert
authors.initials: R
authors.lastname: Capps
authors.forename: Robert
authors.initials: R
authors.lastname: Barham
authors.forename: Gary
authors.initials: G
authors.lastname: Meyer
authors.forename: Katie
authors.initials: K
authors.lastname: Smith
authors.forename: Jacques
authors.initials: J
authors.lastname: Caldwell
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood*; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein; D011623:gamma-Glutamyl Hydrolase / Q000097:blood*
chemical_list: D017931:DNA Primers; D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate