RFC-1 80G>A is a genetic determinant of methotrexate efficacy in Rheumatoid Arthritis: A HuGE review and meta-analysis of observational studies.

Background: Associations have been reported between candidate genes and response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and yielded conflicting results. Systematic reviews of all variants are lacking, and meta-analyses have been reported for only the two most commonly studied variants. Methods: We performed a systematic review of genetic variant associations with MTX efficacy and toxicity and performed meta-analysis of the most commonly studied single nucleotide polymorphism lacking prior cumulative analysis. Studies were identified from the Medline/EMBASE/HuGENET Navigator and the Cochrane Library through December 2012, and the 2009-2011 ACR and EULAR proceedings' abstracts. Additional unpublished genotype data from a Canadian early rheumatoid arthritis cohort were also included. Results: From 87 studies examining genetic association with MTX efficacy and toxicity, Reduced Folate Carrier-1 (RFC-1) 80G>A (Arg27His, rs1051266) was selected for random-effects meta-analysis. RFC-1 80G>A was associated with MTX efficacy using either recessive (OR 1.42, 95%CI: 1.04, 1.93) or additive models (OR 1.28, 95%CI: 1.10, 1.49). Restricting sensitivity analyses to studies involving white subjects using similar outcome measures (MTX failure versus no failure) maintained and improved the associations for both models. No significant association was detected between RFC-1 80G>A and MTX toxicity. Conclusions: RFC-1 80G>A is associated with MTX efficacy but not toxicity in RA patients using available data from observational studies. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in definitions of response in pharmacogenetic studies are sources of data heterogeneity that should be addressed. © 2013 American College of Rheumatology.