Few studies have investigated the correlation between pharmacogenomics and tacrolimus pharmacokinetics in patients with nephrotic syndrome (NS). This study evaluated the influences of genetic polymorphisms of metabolic enzymes, transporters, and podocyte-associated proteins on tacrolimus concentration in Chinese pediatric patients with refractory NS. A total of 167 pediatric patients with refractory NS were included from July 2013 to December 2017. Age of onset was restricted to <14 years of age. Dose-adjusted tacrolimus trough concentration (C0/D) on the third month was calculated, and 20 single-nucleotide polymorphisms in sixteen genes were genotyped. Age was correlated with tacrolimus C0/D (p = 0.006, r = 0.213). Tacrolimus C0/D was higher in CYP3A5 nonexpressers than in CYP3A5 expressers (p = 0.003). ACTN4 rs62121818, MYH9 rs2239781, CYP3A5*3, and age explained 20.5% interindividual variability of tacrolimus concentration in the total cohort. In CYP3A5 nonexpressers, ACTN4 rs62121818 and MYH9 rs2239781 together explained 14.6% variation of tacrolimus C0/D. MYH9 rs2239781, LAMB2 rs62119873 and age together explained 22.3% variability of tacrolimus level in CYP3A5 expressers. CYP3A5*3 was still an important factor affecting tacrolimus concentration in patients with NS. Podocyte-associated gene polymorphisms, especially ACTN4 rs62121818 and MYH9 rs2239781, were the other most important biomarkers for tacrolimus whole blood levels. Genotyping of CYP3A5, ACTN4, and MYH9 polymorphisms may be helpful for better guiding tacrolimus dosing in pediatric patients with refractory NS.
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This research was supported by grants from the National Natural Science Foundation of China (grant no. 81603203), the National Key Research and Development Program (grant no. 2017YFC0909303), the National Key Research and Development Program (grant no. 2016YFC0905001), Health Commission of Guangdong Province (grant no. 2016–568), Guangzhou Women and Children’s Medical Center/Guangzhou Institute of Pediatrics (grant no. YIP-2018–020). We thank the physicians (Fazhan Zhong, Huiying Deng, Fu Zhong, Ye Chen, Huabin Yang, and Zichuan Xu) and nurses (Hui Deng, Yuru Liao) from the division of nephrology for their contribution to patients’ recruitment and sample collection. Thank Caijiao Guo for her concentration determining assistance from the clinical laboratory. Thanks for the help of Fangling Zeng, Bing Zhu, and Yinghua Li from the central lab and Xiaojun Cao and Xu Lin from the department of science and education. Yanling He, Yingjie Li, and Min Huang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of interest
The authors declare that they have no conflict of interest.
The study was performed according to the Declaration of Helsinki and guidelines on good clinical practice, and ethical approval was obtained from the ethics committee of Guangzhou Women and Children’s Medical Center (no. 201509). Written informed consent was obtained from all patients or their guardians before participation. This study was a part of a large clinical trial (NCT02602873), aiming to achieve individualized administration of tacrolimus in patients with pediatric NS.
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Mo, X., Li, J., Liu, Y. et al. Kidney podocyte-associated gene polymorphisms affect tacrolimus concentration in pediatric patients with refractory nephrotic syndrome. Pharmacogenomics J 20, 543–552 (2020). https://doi.org/10.1038/s41397-019-0141-x