SAT0064 Moving Towards Personalized Medicine in Rheumatoid Arthritis: Atic Polymorphisms as Pharmacogenetic Predictors of Methotrexate Therapeutic Outcome
Authors: A. Lima, M. Bernardes, R. Azevedo, R. Medeiros, V. Seabra
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Identifying genetic predictors of methotrexate (MTX) therapeutic outcome in patients with rheumatoid arthritis (RA) may have great importance for a swift moving towards personalized medicine<sup>1,2</sup>. <h3>Objectives</h3> To investigate whether selected polymorphisms in genes relevant for MTX action mechanism (<i>de novo</i> purine synthesis pathway) modulate MTX therapeutic outcome in Portuguese RA patients. <h3>Methods</h3> 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) <i>aminoimidazole-4-carboxiamide ribonucleotide transformylase</i> (<i>ATIC</i>) rs2372536 C&gt;G, rs3821353 G&gt;T, rs4673993 T&gt;C, rs7563206 T&gt;C, rs12995526 T&gt;C and rs16853834 C&gt;T; 2) <i>glycineamide ribonucleotide formyl transferase</i> (<i>GART</i>) rs8971 A&gt;G; and, 3) <i>phosphoribosyl pyrophosphate amidotransferase</i> (<i>PPAT</i>) rs3796548 C&gt;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. <h3>Results</h3> Four SNPs in <i>ATIC</i> 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 <i>ATIC</i> 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 <i>ATIC</i> 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 <i>ATIC</i> 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 <i>ATIC</i> that were significant in BLR, had a 16-fold increased risk for MTX-related toxicity. This risk remained even when adjusted in BLR. <h3>Conclusions</h3> The studied SNPs in <i>ATIC</i> can be considered as pharmacogenetic markers of MTX therapeutic outcome in RA patients, although further studies will be required to validate these findings. <h3>References</h3> 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. <h3>Disclosure of Interest</h3> None declared