title: Role of methotrexate polyglutamation and reduced folate carrier 1 (RFC1) gene polymorphisms in clinical assessment indexes.
abstract: The aims of the present study were to define inter-individual differences in response to methotrexate (MTX) through MTX polyglutamate (MTX-PG) levels in red blood cells (RBC) and MTX-related gene polymorphisms. A total of 145 rheumatoid arthritis patients were recruited. MTX-PG1-5 concentrations in RBC were measured, and 11 single nucleotide polymorphisms, all in MTX-related genes involved in the folate pathway, were analyzed. Disease activity was also assessed. There was no direct relationship between any MTX-PG concentration and the patient's disease condition, but detectability of MTX-PG5 was extracted as a candidate marker for response to MTX. When disease activity was compared between patients in which MTX-PG5 was detectable and undetectable, all indexes except the visual analog scale (VAS) and C-reactive protein (CRP) were found to be significantly lower in the former patients. Reduced folate carrier 1 (RFC1) 80G>A was significantly associated with the detectability of MTX-PG5; detectability of MTX-PG5 was lower in patients with the A mutant allele. The present study suggests that detectability of MTX-PG5 in RBC is a possible biomarker for response to MTX, and the RFC1 80G>A mutation is associated with low detectability of MTX-PG5. Prospective studies with a sufficient number of patients are needed to confirm the present findings.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Kyushu University.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Ando
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: Nozomi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Motohiro
authors.initials: M
authors.lastname: Oribe
authors.forename: Eiji
authors.initials: E
authors.lastname: Otsuka
authors.forename: Kohji
authors.initials: K
authors.lastname: Ishii
authors.forename: Takuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein / Q000235:genetics*
chemical_list: D015415:Biomarkers; D058978:Reduced Folate Carrier Protein; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate