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Effects of splicing-regulatory polymorphisms in ABCC2, ABCG2, and ABCB1 on methotrexate exposure in Chinese children with acute lymphoblastic leukemia

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Abstract

Purpose

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters play an important role in the response to methotrexate (MTX). In this study, we investigated the frequency distribution of three splicing-regulatory polymorphisms in ABC transporters (ABCC2 rs2273697 G>A, ABCG2 rs2231142 G>T, and ABCB1 rs1128503 A>G) and their effects on MTX concentrations and the clinical outcome in a Chinese pediatric population with acute lymphoblastic leukemia (ALL).

Methods

A fluorescence polarization immunoassay was used to measure the serum MTX concentrations in 24 h (C24h) and 42 h (C42h). The Sequenom MassARRAY system was used for single-nucleotide polymorphism (SNP) genotyping.

Results

The study population had significantly lower frequencies of ABCC2 rs2273697 A, ABCG2 rs2231142 G, and ABCB1 rs1128503 G than African and European samples (P < 0.05). The dose-normalized MTX concentrations after 24 h and the proportion of C42h > 0.5 µmol/L were significantly lower in patients with the ABCG2 rs2231142 GG genotype than in patients with the GT or TT genotype (P = 0.01 and 0.006, respectively). No significant effects on MTX pharmacokinetics were observed for ABCC2 rs2273697 and ABCB1 rs1128503 polymorphisms. Bioinformatics analysis suggested that the three SNPs overlapped with the putative binding sites of several splicing factors.

Conclusion

In conclusion, our study confirmed the ethnicity-based differences in the distribution of the three investigated SNPs. The ABCG2 rs2231142 polymorphism exerted a significant effect on the level of MTX exposure. These findings may help explain the variability in MTX responses and optimize MTX treatment in pediatric patients with ALL.

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Available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Bullet Edits Limited for proofreading the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant numbers 81872926 and 81503135) and Beijing Municipal Administration of Hospitals’ Youth Program (Grant number QML20160703).

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Authors and Affiliations

  1. Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China

    Miao Li

  2. Department of Pharmacy, Armed Police Beijing Corps Hospital, Beijing, 100027, China

    Xiao-Yan Kong

  3. Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, No 10 Tieyi Road, Yangfangdian, Haidian District, Beijing, 100038, China

    Shu-Mei Wang

  4. Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China

    Shu-Mei Wang

  5. International Cooperation and Joint Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China

    Shu-Mei Wang

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Li, M., Kong, XY. & Wang, SM. Effects of splicing-regulatory polymorphisms in ABCC2, ABCG2, and ABCB1 on methotrexate exposure in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 91, 77–87 (2023). https://doi.org/10.1007/s00280-022-04498-0

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