Role of Methotrexate Polyglutamation and Reduced Folate Carrier 1 (RFC1) Gene Polymorphisms in Clinical Assessment Indexes

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-PG(1-5) 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-PG(5) was extracted as a candidate marker for response to MTX. When disease activity was compared between patients in which MTX-PG(5) 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-PG(5); detectability of MTX-PG(5) was lower in patients with the A mutant allele. The present study suggests that detectability of MTX-PG(5) in RBC is a possible biomarker for response to MTX, and the RFC1 80G>A mutation is associated with low detectability of MTX-PG(5). Prospective studies with a sufficient number of patients are needed to confirm the present findings.