Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

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.

Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway

“…Thus, in a recent study of Caucasian RA patients, the frequency of the TYMS 2R allele has been reported to be 0.41 [52] and we found a frequency of 0.63 in our study. The discordance between the results could also be explained by the variation of TYMS gene copy number due to loss of heterozygosis or gene amplification as reported by Uchida et al (2004) in patients with colorectal cancer treated by 5-fluorouracilbased therapy [53].…”

Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Hospital-Based Cohort Study

“…In addition, the 3R/3R genotype among patients with the TYMS 5′-UTR 28-bp tandem repeat was associated with a better MTX therapeutic response than the 2R allele, although the difference was not slightly significant. The same tendency was found by James et al, 44) but the opposite result was reported by Lima et al 45) For the TYMS 5′-UTR 28-bp tandem repeat, it was reported that 3R compared with 2R increased the level of mRNA expression, 46,47) and MTX dosage increases in patients with the 3R allele achieved the same therapeutic effect as in those without 3R allele. 48) However, this study did not examine differences in the MTX dose required among TYMS 5′-UTR genotypes.…”

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

“…The allele with two repeats (2R) has been shown to cause decreased translation of TYMS relative to the three-repeat (3R) allele [55], but the exact mechanism is not fully known. It has been reported that patients with rheumatoid arthritis and TYMS 3R3R genotype show a weaker response to MTX therapy [56]. The 3 UTR region of the TYMS gene contains and 6bp-long indel.…”