Impact of combined CYP3A4 and CYP3A5 single- nucleotide polymorphisms on tacrolimus exposure and acute rejection in Egyptian pediatric kidney transplant recipients: single center experience

Abstract Background Tacrolimus is the cornerstone of immunosuppressive therapy in pediatric kidney transplantation. Single-nucleotide polymorphisms (SNPs) in genes that code for the tacrolimus-metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5 significantly impact tacrolimus pharmacokinetics. The aim of this study is to assess the effect of CYP3A4 and 5 gene polymorphisms on tacrolimus levels and their impact on the risk of rejection in a cohort of Egyptian pediatric kidney transplant recipients. Methods This case–control study included 146 children: 66 pediatric kidney transplant recipients (KTR) following at a pediatric kidney transplant outpatient clinic at Cairo University Children's Hospital and 80 age- and sex-matched healthy control children. All patients and controls ( n = 146) were genotyped for CYP3A5 6986A > G (rs776746) polymorphism and CYP3A4*1B-392A > G (rs2740574) polymorphism using deoxyribonucleic acid (DNA) extraction and then amplified by PCR, followed by gel electrophoresis. The KTRs ( n = 66) were divided into acute rejection (AR) and non-AR groups and compared regarding genotypes, tacrolimus doses, concentration, and concentration/dose (C/D) ratio. Results The frequency of CYP3A5-6986A > G 1/3 polymorphism was significantly higher in the AR group than in the non-AR and control groups, with p -values of 0.006 and < 0.001, respectively. There was a significant association between the CYP3A5-6986A > G allele 1 and acute rejection ( p -value: 0.03, OR: 2.4). Consequently, the risk of acute graft rejection is higher for this group of pediatric recipients. Children with CYP3A5-6986A > G 1/3 polymorphism required a significantly higher tacrolimus dose to reach the target trough level and had a significantly lower tacrolimus CD ratio than CYP3A5-6986A > G 3 polymorphism, with p -values of 0.03 and 0.04, respectively. Regarding the CYP3A4gene, it was noticed that there was a higher frequency of CYP3A4*1B-392A > G (AA) polymorphism in the AR group (33%, n = 10/30) and CYP3A4*1B-392A > G (GG) polymorphism in the non-AR group (41%, n = 15/36), but the difference was not significant. Conclusion CYP3A gene polymorphism has an impact on the graft function and incidence of rejection, especially CYP3A5-6986A > G 1/3 polymorphism, through their effect on tacrolimus levels. Therefore, it is recommended to do CYP3A gene polymorphism for pediatric kidney transplant recipients to adjust their tacrolimus dosage appropriately.