S-M Wang1,2, W-X Zeng1,2, W-S Wu3, L-L Sun2, D Yan1,2. 1. Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. 2. Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. 3. Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Abstract
WHAT IS KNOWN AND OBJECTIVE: Thymidylate synthase (TYMS) is an important target for methotrexate (MTX). Genetic variations in the TYMS gene contribute to the differences in treatment responses to MTX. The aim of this study was to investigate the distribution of a microRNA (miRNA) binding site polymorphism (rs2790 A > G) in the 3'-untranslated region (3'-UTR) of TYMS and its association with MTX concentration and haematological toxicity in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL). METHODS: The Sequenom MassARRAY system was used for TYMS rs2790 A > G genotyping in 118 children with ALL. Serum MTX concentrations were measured by a fluorescence polarization immunoassay. Clinical data were extracted from the electronic medical records. RESULTS AND DISCUSSION: The minor allele frequency noted in this study (39.8%) was significantly higher than those in the CEU (Utah residents with northern and western Europe ancestry; 16.2%) and YRI (Yoruba in Ibadan, Nigeria; 25.0%) samples reported in the 1000 Genomes Project (P < .01). The frequency of MTX level >40 μmol/L at 24 hours in patients with the AA genotype (36.6%) was significantly higher than that in GG genotype carriers (5.9%, P < .05). However, the incidence rates of haematological toxicity were similar in the three genotype groups. Whereas there was evidence of higher blood levels in the A homozygotes, the evidence for this translating to higher toxicity was lacking. A larger study would be required to answer this. WHAT IS NEW AND CONCLUSION: The results of this study confirmed the significant ethnic differences in the distributions of the TYMS rs2790 A > G polymorphism. Whereas there was evidence of differences in MTX blood levels according to genotype, our study was not powered to show whether this would lead to more haematological toxicity.
WHAT IS KNOWN AND OBJECTIVE:Thymidylate synthase (TYMS) is an important target for methotrexate (MTX). Genetic variations in the TYMS gene contribute to the differences in treatment responses to MTX. The aim of this study was to investigate the distribution of a microRNA (miRNA) binding site polymorphism (rs2790 A > G) in the 3'-untranslated region (3'-UTR) of TYMS and its association with MTX concentration and haematological toxicity in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL). METHODS: The Sequenom MassARRAY system was used for TYMSrs2790 A > G genotyping in 118 children with ALL. Serum MTX concentrations were measured by a fluorescence polarization immunoassay. Clinical data were extracted from the electronic medical records. RESULTS AND DISCUSSION: The minor allele frequency noted in this study (39.8%) was significantly higher than those in the CEU (Utah residents with northern and western Europe ancestry; 16.2%) and YRI (Yoruba in Ibadan, Nigeria; 25.0%) samples reported in the 1000 Genomes Project (P < .01). The frequency of MTX level >40 μmol/L at 24 hours in patients with the AA genotype (36.6%) was significantly higher than that in GG genotype carriers (5.9%, P < .05). However, the incidence rates of haematological toxicity were similar in the three genotype groups. Whereas there was evidence of higher blood levels in the A homozygotes, the evidence for this translating to higher toxicity was lacking. A larger study would be required to answer this. WHAT IS NEW AND CONCLUSION: The results of this study confirmed the significant ethnic differences in the distributions of the TYMSrs2790 A > G polymorphism. Whereas there was evidence of differences in MTX blood levels according to genotype, our study was not powered to show whether this would lead to more haematological toxicity.