Pharmacogenetics of CYP3A4, CYP3A5, CYP2C8 and CYP2C19 and Their Influence on Tacrolimus Pharmacokinetics in Renal Transplant Recipients

Abstract

Tacrolimus (TAC) is an established essential immunosuppressive agent for renal transplant recipients. Its complex metabolism leads to the various short-term and long-term post-transplant complications. Our study aims to investigate the pharmacogenetics of CYP3A4, CYP3A5, CYP2C8 and CYP2C19 and their influence on tacrolimus pharmacokinetics (PKs) in short-term renal transplant recipients. A total 105 renal transplant recipients meted our inclusion criteria and their TAC-related information on 7days, 14days, 30days, 3months, 6months and more than 12months were extracted. Blood samples were collected and total DNA were extracted. Whole-exome sequencing (WES) based on next-generation sequencing technology was used to detect all exons, exon/intron boundaries and flanking regions of CYP3A4, CYP3A5, CYP2C8 and CYP2C19. After adjustment of minor allele frequencies MAF and Hardy–Weinberg equilibrium (HWE) analysis, tagger single nucleotide polymorphisms (SNPs) and haplotypes were identified. Influence of tagger SNPs on the TAC concentrations were analyzed and multivariable regression analysis was performed to investigate the influence of clinical variables on the TAC levels. Furthermore, general linear model was used to explore the effect of haplotypes on the TAC pharmacokinetics. As a result, a total 94 SNPs were identified in WES analysis. After MAF, HWE and linkage disequilibrium analysis, 9 tagger SNPs were selected and 4 of these SNPs (rs15524, rs2242480, rs4646453 and rs4917623) were found to be significantly associated with the TAC PKs in short-term post-transplant follow-up. Moreover, TAC measurement time points, body mass index (BMI), usage of sirolimus, incidence of delayed graft function (DGF) were observed to be significantly associated with the TAC PKs. Three haplotypes were identified and rs15524-rs 4646453 was found to remarkably contribute to the TAC PKs. Furthermore, recipients carrying H2/H2 (GG-AA) haplotype showed significantly higher weight-and dose-adjusted TAC concentrations in post-transplant 7days, 14days, 30days, 3months and 6 months. In conclusions, we reported four tagger SNPs, including rs15524, rs2242480, rs4646453 and rs4917623, were significantly related to the variability of the TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, incidence of DGF contributed to this influence. In addition, recipients carrying H2/H2 (GG-AA) haplotype in rs15524-rs 4646453 may require lower dosage of TAC during the post-transplant 1-year follow-up.