Abstract
The aim of this study was to identify novel genetic variants affecting tacrolimus trough blood concentrations. We analyzed the association between 58 single nucleotide polymorphisms (SNPs) across the CYP3A gene cluster and the log-transformed tacrolimus concentration/dose ratio (log (C0/D)) in 819 renal transplant recipients (Discovery cohort). Multivariate linear regression was used to test for associations between tacrolimus log (C0/D) and clinical factors. Luciferase reporter gene assays were used to evaluate the functions of select SNPs. Associations of putative functional SNPs with log (C0/D) were further tested in 631 renal transplant recipients (Replication cohort). Nine SNPs were significantly associated with tacrolimus log (C0/D) after adjustment for CYP3A5*3 and clinical factors. Dual luciferase reporter assays indicated that the rs4646450 G allele and rs3823812 T allele were significantly associated with increased normalized luciferase activity ratios (p < 0.01). Moreover, CYP3A7*2 was associated with higher TAC log(C0/D) in the group of CYP3A5 expressers. Age, serum creatinine and hematocrit were significantly associated with tacrolimus log (C0/D). CYP3A7*2, rs4646450, and rs3823812 are proposed as functional SNPs affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients. Clinical factors also significantly affect tacrolimus metabolism.
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Acknowledgements
We would like to give special thanks to all the renal transplant recipients involved in this study. This work was supported by the Natural Science Fund of Guangdong, China (2018A0303130186&2019A1515010100), the Guangdong Science and Technology Foundation (2019B030316032), the Guangxi Natural Science Foundation (2020GXNSFAA159161), and Southern Medical University Innovation Training Program for Undergraduate Students (201812121005&202012121010). Genotype-tissue expression (GTEx) Project was supported by common fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from GTEx Analysis Release V7, dbGaP Accession phs000424.v7.p2.
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DC, HL, and LQL conducted the experiments and drafted the paper. WGS, JX, TY, SY, PZ, YC, JC, WX, QL, QZ, DY, WQ, and LSL collected the samples and data. WS and DW revised the paper. CL and LL designed the study. All authors reviewed and approved the paper.
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Chen, D., Lu, H., Sui, W. et al. Functional CYP3A variants affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients. Pharmacogenomics J 21, 376–389 (2021). https://doi.org/10.1038/s41397-021-00216-w
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DOI: https://doi.org/10.1038/s41397-021-00216-w
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