THU0457 Tyms Polymorphisms and Methotrexate Therapeutic Outcome in Rheumatoid Arthritis Portuguese Patients: Analysis of Key Polymorphisms
Authors: A. Lima, V. Seabra, M. Bernardes, A.R. Azevedo, H. Sousa, R. Medeiros
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) could be conditioned by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (<i>TYMS</i>) [1,2]. <h3>Objectives</h3> The aim of this study was to elucidate the clinical relevance of three <i>TYMS</i> polymorphisms, using genotype and haplotype-based approaches, in MTX therapeutic outcome (regarding both response and overall toxicity) in Portuguese RA patients. <h3>Methods</h3> This study included 233 Caucasian RA patients treated with MTX. Clinicopathological data were collected, outcomes were defined and patients were genotyped using polymerase chain reaction-restriction fragment length polymorphism or sequencing technology for the following <i>TYMS</i> polymorphisms: 1)28 base pairs (bp) variable number tandem repeat (rs34743033); 2)single nucleotide polymorphism (SNP) C&gt;G (rs2853542); and 3)6bp sequence deletion (1494del6, rs34489327). For statistical analysis, chi-square and binary logistic regression analyses were performed. Haplotype analyses were used to better understand the contribution of <i>TYMS</i> in MTX therapeutic outcome. <h3>Results</h3> Considering <i>TYMS</i> genotypes, 3R homozygotes (<i>p</i>=0.005;OR=2.34), 3RC3RG genotype (<i>p</i>=0.016;OR=3.52) and 6bp- carriers (<i>p</i>=0.011;OR=1.96) were associated with non-response to MTX, when compared to 2R carriers, 2R3RG and 6bp+ homozygotes, respectively. Multivariate analyses confirmed the increased risk for non-response to MTX in 6bp- carriers (<i>p</i>=0.020;OR=2.40). <i>TYMS</i> polymorphisms were in linkage disequilibrium in our population (<i>p</i>&lt;0.00001) and alleles 2R and 6bp+ were the most frequent and linked ones (<i>D9</i>=0.67). The haplotype analysis revealed that 3R6bp- (<i>p</i>=0.001;OR=2.54), 3RC6bp+ (<i>p</i>=0.041;OR=1.79), 3RC6bp- (<i>p</i>=0.013;OR=2.80) and 3RG6bp- (<i>p</i>=0.009;OR=2.39) were associated with non-response to MTX when compared to 2R6bp+ haplotype. Multivariate analysis demonstrated that 3R6bp- (<i>p</i>=0.012;OR=2.68), 3RC6bp- (<i>p</i>=0.048;OR=2.89) and 3RG6bp- (<i>p</i>=0.043;OR=2.60) were associated with non-response to MTX when compared to 2R6bp+. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to <i>TYMS</i> genotypes and haplotypes. <h3>Conclusions</h3> <i>TYMS</i> polymorphisms seem to be important to help predicting clinical response to MTX in RA patients and not important in predicting MTX-related toxicity. Moreover, the effect of <i>TYMS</i> 1494del6 polymorphism in clinical response is possibly stronger. Despite the potential of these findings, translation into clinical practice needed larger studies to provide positive confirmation. <h3>References</h3> Lima A, Azevedo R, Sousa H, Seabra V, Medeiros R (2013) Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. Pharmacogenomics 14 (11):1337-1351. Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N. Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med. 2003 May;11(5):593-600. <h3>Acknowledgements</h3> The authors wish to acknowledge to <i>Fundação para a Ciência e Tecnologia</i> (FCT) for the Doctoral Grant (SFRH/BD/64441/2009) for Aurea Lima and also to the nursing service of Rheumatology Day Hospital of São João Hospital Center and the clinicians from the Rheumatology Department of São João Hospital Center. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4672