Abstract
The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.
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Acknowledgements
This work was supported by the National Key Research and Development Program (No 2016YFC0905000), the National High Technology Research and Development Program of China, the “863” Project (No 2012AA02A518), the National Natural Science Foundation of China (No 81522048, 81573511, and 81273595), and the Innovation Driven Project of Central South University (No 2016CX024).
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Supplementary information is available at website of Acta Pharmacologica Sinica.
Supplementary information
Supplementary Figure S1
Consort diagram of patients selection (JPG 270 kb)
Supplementary Table S1
Clinical characteristics of recipients based on rs2242480 genotypes. (DOC 42 kb)
Supplementary Table S2
Clinical characteristics of recipients based on rs4646437 genotypes. (DOC 44 kb)
Supplementary Table S3
Clinical characteristics of recipients based on rs181781 genotypes. (DOC 43 kb)
Supplementary Table S4
Clinical characteristics of recipients based on rs1641536 genotypes. (DOC 43 kb)
Supplementary Table S5
Clinical characteristics of recipients based on rs776746 genotypes. (DOC 43 kb)
Supplementary Table S6
Clinical characteristics of recipients based on rs4553808 genotypes. (DOC 43 kb)
Supplementary Table S7
Clinical characteristics: CYP 3A5 rs776746 (AA&AG vs GG). (DOC 43 kb)
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Liu, Mz., He, Hy., Zhang, Yl. et al. IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacol Sin 38, 415–423 (2017). https://doi.org/10.1038/aps.2016.153
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DOI: https://doi.org/10.1038/aps.2016.153
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