Association of Genetic Variants in CYP3A4, CYP3A5, CYP2C8, and CYP2C19 with Tacrolimus Pharmacokinetics in Renal Transplant Recipients

Abstract

Background: Our study aimed to investigate the pharmacogenetics of cytochrome P3A4 (CYP3A4), CYP3A5, CYP2C8, and CYP2C19 and their influence on TAC Pharmacokinetics (PKs) in short-term renal transplant recipients. Method: A total of 105 renal transplant recipients were enrolled. Target Sequencing (TS) 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 TAC concentrations was analyzed. Results: A total of 94 SNPs were identified in TS analysis. Nine tagger SNPs were selected, and two SNPs (rs15524 and rs4646453) were noted to be significantly associated with TAC PKs in short-term post-transplant follow-up. Measurement time points of TAC, body mass index (BMI), usage of sirolimus, and incidence of Delayed Graft Function (DGF) were observed to be significantly associated with TAC PKs. Three haplotypes were identified, and rs15524-rs4646453 was found to remarkably contribute to TAC PKs. Recipients carrying H2/H2 (GG-AA) haplotype also showed significantly high weight- and dose-adjusted TAC concentrations in posttransplant periods of 7, 14, and 30 days and 3 and 6 months. Conclusions: Two tagger SNPs, namely, rs15524 and rs4646453, are significantly related to the variability of TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, and incidence of DGF contribute to this influence. Recipients carrying H2/H2 (GG-AA) haplotype in rs15524–rs4646453 may require a low dosage of TAC during 1-year follow-up posttransplant.