Abstract
BackgroundTherapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients.MethodsClinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches.ResultsConsidering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes.ConclusionOur study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.
Highlights
Methotrexate (MTX) is the cornerstone for rheumatoid arthritis (RA) treatment and is the most widely used disease-modifying antirheumatic drug (DMARD) in newly diagnosed patients [1,2]
Since thymidylate synthase (TS) levels were found to be predictive of MTX therapeutic outcome [13,14] and genetic polymorphisms in TS gene (TYMS) have been associated with TS levels [15,16], pharmacogenomics has raised great interest and, some studies have attempted to clarify the influence of genetic variations on clinical response to MTX in RA [17]
Every 3 months treatment response was evaluated and, on the: 1) first evaluation, if patients have no response or show gastrointestinal toxicity, administration route was changed to subcutaneous (SC); 2) second evaluation, if maximum tolerable dose was used without response, MTX therapy was discontinued or associated with other synthetic DMARD; and 3) third evaluation, in patients without response and other contraindication, therapy was changed by associating a biological DMARD
Summary
Methotrexate (MTX) is the cornerstone for rheumatoid arthritis (RA) treatment and is the most widely used disease-modifying antirheumatic drug (DMARD) in newly diagnosed patients [1,2]. In the presence of cytosine (3RC) the E-box seems to be disrupted, reducing the stimulation of transcription in comparison to 3RG, thereby decreasing TS levels [15] Since this SNP occurs within the TYMS 28 bp VNTR polymorphism, several studies have been performed combining the information from both TYMS enhancer region (TSER) polymorphisms [6,21]. Another important polymorphism is a 6 bp sequence (TTAAAG) deletion (1494del, rs34489327) at 39UTR, which seems to affect a region of TS premessenger ribonucleic acid (mRNA) that contains cis adenylateuridylate-rich elements (AREs) [22,23]. This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients
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