Background Identifying genetic predictors of methotrexate (MTX) therapeutic outcome in patients with rheumatoid arthritis (RA) may have great importance for a swift moving towards personalized medicine1,2.
Objectives To investigate whether selected polymorphisms in genes relevant for MTX action mechanism (de novo purine synthesis pathway) modulate MTX therapeutic outcome in Portuguese RA patients.
Methods In a group of 233 Caucasian RA patients treated with MTX, clinicopathological data were collected and outcomes defined. Patients were genotyped for 8 single nucleotide polymorphisms (SNPs): 1) aminoimidazole-4-carboxiamide ribonucleotide transformylase (ATIC) rs2372536 C>G, rs3821353 G>T, rs4673993 T>C, rs7563206 T>C, rs12995526 T>C and rs16853834 C>T; 2) glycineamide ribonucleotide formyl transferase (GART) rs8971 A>G; and, 3) phosphoribosyl pyrophosphate amidotransferase (PPAT) rs3796548 C>T. Univariate analyses and binary logistic regressions (BLR) adjusted to possible confounder variables were performed by using genotype and haplotype-based approaches. Genetic (GRI) and toxicogenetic (TRI) risk indexes were created.
Results Four SNPs in ATIC were associated with about 3-fold increased risk for a non-response profile to MTX: rs2372536 G carriers, rs4673993 T carriers, rs7563206 T carriers and rs12995526 T carriers. After adjusting in a BLR, genotypes remained significant. All SNPs in ATIC were in linkage disequilibrium except for rs3821353 and rs16853834 and analyses were performed considering the following combinations: 1. rs2372536, rs3821353, rs4673993, rs7563206 and rs12995526; and 2. rs2372536, rs4673993, rs7563206, rs12995526 and rs16853834. Haplotypes CGTTT for combination 1. and CTTTC for combination 2. were associated with a non-response profile. The BLR was only significant for CGTTT haplotype when compared to CTCCC. The GRI revealed that patients with 4 risk variants, i.e. with the 4 genotypes in ATIC that were statistically significant in BLR, had a 2-fold increased risk for a non-response profile. When adjusted in BLR, results were not confirmed. Two SNPs in ATIC were associated with about 2-fold risk for MTX-related toxicity: rs7563206 CC and rs12995526 CC. After adjusting in a BLR, the genotypes remained significant and 2 others demonstrated a borderline association with MTX-related toxicity (rs2372536 G carriers and rs3821353 T carriers). Haplotype CTTCC for combination 1. was associated with MTX-related toxicity only when adjusted in BLR. The TRI revealed that patients with 4 risk variants, i.e. with the 4 genotypes in ATIC that were significant in BLR, had a 16-fold increased risk for MTX-related toxicity. This risk remained even when adjusted in BLR.
Conclusions The studied SNPs in ATIC can be considered as pharmacogenetic markers of MTX therapeutic outcome in RA patients, although further studies will be required to validate these findings.
Romao VC, et al. Three decades of low-dose methotrexate in rheumatoid arthritis: Can we predict toxicity? Immunol Res 2014;60(2-3):289-310.
Lima A, et al. Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers. Pharmacogenomics 2014;15(12):1611-35.
Disclosure of Interest None declared