PLoS One. 2014 Oct 3;9(10):e108165. doi: 10.1371/journal.pone.0108165. eCollection 2014.

Role of key TYMS polymorphisms on methotrexate therapeutic outcome in portuguese rheumatoid arthritis patients.

Lima A¹, Seabra V², Bernardes M³, Azevedo R⁴, Sousa H⁵, Medeiros R⁶.

Author information

1: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Gandra PRD, Portugal; Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal.
2: CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences-North (ISCS-N), Gandra PRD, Portugal.
3: Faculty of Medicine of University of Porto (FMUP), Porto, Portugal; Rheumatology Department of São João Hospital Center, Porto, Portugal.
4: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Faculty of Medicine of University of Porto (FMUP), Porto, Portugal.
5: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Faculty of Medicine of University of Porto (FMUP), Porto, Portugal; Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal.
6: Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal; Virology Service, Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Research Department-Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal.

Abstract

BACKGROUND:

Therapeutic 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.

METHODS:

Clinicopathological 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.

RESULTS:

Considering 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.

CONCLUSION:

Our 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.