The pharmacogenomics journal. 2013;13(3):227-234.
We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate
(MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1
(RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient
cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with
predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were
detected with efficacy (P-trend 0.05) including four SNPs in the ATIC gene (rs12995526,
rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425,
rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the
GGH gene (rs12681874). Five SNPs were significantly associated with adverse events;
three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline
significance in the FPGS gene. The results suggest that genetic variations in several
key MTX pathway genes may influence response to MTX in the RA patients. Further studies
will be required to validate these findings and if confirmed these results could contribute
towards a better understanding of and ability to predict MTX response in RA.The Pharmacogenomics
Journal advance online publication, 27 March 2012; doi:10.1038/tpj.2012.7.