CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria

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Abstract

Purpose

The purpose of this study was to investigate the potential impact of CYP3A4, CYP3A5, and CYP3A7 polymorphisms on the concentration and efficacy of tacrolimus in a cohort of pediatric patients with nephrotic range proteinuria.

Methods

Genetic variants including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), rs4646437, and CYP3A7 rs2257401 and rs10211 were detected in 70 pediatric patients with nephrotic range proteinuria. The relationships of dose-adjusted trough concentration (C0) of tacrolimus with corresponding genotypes were investigated.

Results

The tacrolimus concentration in patients without CYP3A5*3 A allele was 94% higher than those with A allele (90.7 vs 54.2, P = 0.00006). The CYP3A7 rs2257401 was also associated with the concentration of tacrolimus. The C allele carriers had an obviously lower C0 than the non-carriers (62.4 vs 90.7, P = 0.001). In addition, there were significant differences in tacrolimus concentration among CYP3A7 rs10211 G carriers and non-carriers; the latter had an almost twofold C0 of the former (101.8 vs 59.6, P = 0.0004).

Conclusions

Our study demonstrated the associations between CYP3A5*3, CYP3A7 rs2257401 and rs10211, and tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Children with CYP3A5*3 A, CYP3A7 rs2257401 C, and rs10211 G alleles might need a higher dose of tacrolimus.

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  • 30 January 2021

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Funding

Hongxia Liu had financial support from the Shanghai Municipal Commission of Health and Family Planning (No. 20164Y0122). Dr. Xiaoyan Qiu had support from the Shanghai “Rising Stars of Medical Talent” Youth Development Program-Clinical Pharmacist Program, National Natural Science Foundation of China (No. 81302854), and Natural Science Foundation of Shanghai (No. 13ZR1405200).

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Authors

Contributions

Hongxia Liu and Qinxia Xu contributed equally to this article. Xiaoyan Qiu and Huajun Sun conceived the study. Xiaoyan Qiu, Qinxia Xu, and Hongxia Liu participated in the research design. Hongxia Liu, Xinyu Kuang, Wenyan Huang, and Qi Zhao contributed to the acquisition of the patients’ data. Zhihu Jiang and Zhiling Li performed the CYP3A5*3 genotyping. Qinxia Xu performed the research and analyzed the data. Xiaoyan Qiu and Qinxia Xu drafted. All the authors revised the manuscript.

Corresponding authors

Correspondence to Huajun Sun or Xiaoyan Qiu.

Ethics declarations

The study was performed in accordance with the Declaration of Helsinki and its amendments. Protocols were approved by the Ethics Committee of Shanghai Children’s Hospital and written informed consents were obtained from all subjects.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with animals performed by any of the authors.

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Liu, H., Xu, Q., Huang, W. et al. CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Eur J Clin Pharmacol 75, 1533–1540 (2019). https://doi.org/10.1007/s00228-019-02726-w

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Keywords

  • CYP3A5
  • CYP3A7
  • Polymorphisms
  • Tacrolimus
  • Pediatric patients
  • Nephrotic range proteinuria