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Functional CYP3A variants affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients

The Pharmacogenomics Journal volume 21, pages 376–389 (2021)Cite this article

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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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Fig. 1: Structure of the CYP3A gene cluster locus.
Fig. 2: Box-and-whisker plots of nine SNPs significantly associated with TAC log (C0/D) after adjusting for CYP3A5*3.
Fig. 3: Luciferase Reporter gene activity assays.
Fig. 4: Allele-specific expression analysis of rs4646450 and rs3823812.
Fig. 5: Distribution of TAC C0/D in two cohorts by diplotypes of four functional SNPs.

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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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  1. These authors contributed equally: Dina Chen, Huijie Lu, Weiguo Sui

Authors and Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Dina Chen, Huijie Lu, Liqing Li, Tengfei Yang, Siyao Yang, Que Zheng, Demei Ye, Wanying Qian & Liang Li

  2. Guangxi Key laboratory of Metabolic Diseases Research, Nephrology Department of Guilin NO. 924 Hospital, Guilin, Guangxi, China

    Weiguo Sui, Jiejing Chen, Wen Xue & Liusheng Lai

  3. Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Jian Xu

  4. Department of Pharmacy, Nanfang hospital, Southern Medical University, Guangzhou, Guangdong, China

    Ping Zheng & Yan Chen

  5. Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Qingping Li & Chuanjiang Li

  6. Center for Pharmacogenomics, Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH, USA

    Wolfgang Sadee

  7. Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Danxin Wang

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Contributions

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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Correspondence to Chuanjiang Li or Liang Li.

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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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