Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia
Background The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and...
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Published in | The journal of gene medicine Vol. 19; no. 11; pp. 353 - 359 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
Wiley Periodicals Inc
01.11.2017
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Abstract | Background
The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3′‐untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL.
Methods
Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h (C24h) and 42 h (C42h) after administration. The effects of the polymorphisms on concentration‐to‐dose (C/D) ratios of MTX were assessed.
Results
Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r2 = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C/D ratios of MTX at 24 and 42 h for the TTC/TTC‐A/A haplotype carriers (11.74 and 0.07 μmol/l per g/m2, respectively) were significantly lower than those in DEL/DEL‐G/G or DEL/TTC‐G/G haplotype carriers (12.49 and 0.09 μmol/l per g/m2, respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs.
Conclusions
The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post‐transcriptional regulation of MTHFR. |
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AbstractList | Background
The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3′‐untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL.
Methods
Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h (C24h) and 42 h (C42h) after administration. The effects of the polymorphisms on concentration‐to‐dose (C/D) ratios of MTX were assessed.
Results
Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r2 = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C/D ratios of MTX at 24 and 42 h for the TTC/TTC‐A/A haplotype carriers (11.74 and 0.07 μmol/l per g/m2, respectively) were significantly lower than those in DEL/DEL‐G/G or DEL/TTC‐G/G haplotype carriers (12.49 and 0.09 μmol/l per g/m2, respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs.
Conclusions
The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post‐transcriptional regulation of MTHFR. Abstract Background The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3′‐untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL. Methods Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h ( C 24h ) and 42 h ( C 42h ) after administration. The effects of the polymorphisms on concentration‐to‐dose ( C / D ) ratios of MTX were assessed. Results Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms ( r 2 = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C / D ratios of MTX at 24 and 42 h for the TTC/TTC‐A/A haplotype carriers (11.74 and 0.07 μmol/l per g/m 2 , respectively) were significantly lower than those in DEL/DEL‐G/G or DEL/TTC‐G/G haplotype carriers (12.49 and 0.09 μmol/l per g/m 2 , respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs. Conclusions The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post‐transcriptional regulation of MTHFR. BACKGROUNDThe pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3'-untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL.METHODSGenotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h (C24h ) and 42 h (C42h ) after administration. The effects of the polymorphisms on concentration-to-dose (C/D) ratios of MTX were assessed.RESULTSComplete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r2 = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C/D ratios of MTX at 24 and 42 h for the TTC/TTC-A/A haplotype carriers (11.74 and 0.07 μmol/l per g/m2 , respectively) were significantly lower than those in DEL/DEL-G/G or DEL/TTC-G/G haplotype carriers (12.49 and 0.09 μmol/l per g/m2 , respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs.CONCLUSIONSThe rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post-transcriptional regulation of MTHFR. The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3'-untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL. Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h (C ) and 42 h (C ) after administration. The effects of the polymorphisms on concentration-to-dose (C/D) ratios of MTX were assessed. Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C/D ratios of MTX at 24 and 42 h for the TTC/TTC-A/A haplotype carriers (11.74 and 0.07 μmol/l per g/m , respectively) were significantly lower than those in DEL/DEL-G/G or DEL/TTC-G/G haplotype carriers (12.49 and 0.09 μmol/l per g/m , respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs. The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post-transcriptional regulation of MTHFR. Background The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G > A and rs35134728 DEL/TTC) in the 3'-untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL. Methods Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24 h (C24h) and 42 h (C42h) after administration. The effects of the polymorphisms on concentration-to-dose (C/D) ratios of MTX were assessed. Results Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r2 = 1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p < 0.01). The C/D ratios of MTX at 24 and 42 h for the TTC/TTC-A/A haplotype carriers (11.74 and 0.07 µmol/l per g/m2, respectively) were significantly lower than those in DEL/DEL-G/G or DEL/TTC-G/G haplotype carriers (12.49 and 0.09 µmol/l per g/m2, respectively; p < 0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs. Conclusions The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post-transcriptional regulation of MTHFR. |
Author | Sun, Lu‐Lu Wang, Shu‐Mei Yan, Dan Zeng, Wei‐Xin Wu, Wan‐Shui |
Author_xml | – sequence: 1 givenname: Shu‐Mei orcidid: 0000-0001-9121-8168 surname: Wang fullname: Wang, Shu‐Mei email: wangshumei1980@126.com organization: Capital Medical University – sequence: 2 givenname: Wei‐Xin surname: Zeng fullname: Zeng, Wei‐Xin organization: Capital Medical University – sequence: 3 givenname: Wan‐Shui surname: Wu fullname: Wu, Wan‐Shui organization: Capital Medical University – sequence: 4 givenname: Lu‐Lu surname: Sun fullname: Sun, Lu‐Lu organization: Capital Medical University – sequence: 5 givenname: Dan surname: Yan fullname: Yan, Dan email: yd277_1@126.com organization: Capital Medical University |
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Keywords | methotrexate microRNA methylenetetrahydrofolate reductase acute lymphoblastic leukemia genetic polymorphism |
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The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia... The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim... Abstract Background The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic... Background The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia... BACKGROUNDThe pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL).... |
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SubjectTerms | 3' Untranslated regions Acute lymphoblastic leukemia Binding sites Children Computer applications Fluorescence Fluorescence polarization Gene frequency Gene regulation Gene therapy genetic polymorphism Genomes Genotyping Haplotypes Immunoassay Leukemia Linkage disequilibrium Lymphatic leukemia Methotrexate Methylenetetrahydrofolate reductase microRNA MicroRNAs miRNA Pediatrics Pharmacokinetics Population genetics Population studies Post-transcription |
Title | Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia |
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