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Background <p>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.</p> Methods <p>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.&#xa0;All patients and controls (<i>n</i> = 146) were genotyped for <i>CYP3A5 6986A</i> &gt; <i>G (rs776746)</i> polymorphism and <i>CYP3A4*1B-392A</i> &gt; <i>G (rs2740574)</i> polymorphism using deoxyribonucleic acid (DNA) extraction and then amplified by PCR, followed by gel electrophoresis. The KTRs (<i>n</i> = 66) were divided into acute rejection (AR) and non-AR groups and compared regarding genotypes, tacrolimus doses, concentration, and concentration/dose (C/D) ratio.</p> Results <p>The frequency of <i>CYP3A5-6986A</i> &gt; <i>G 1/3</i> polymorphism was significantly higher in the AR group than in the non-AR and control groups, with <i>p</i>-values of 0.006 and &lt; 0.001, respectively.&#xa0;There was a significant association between <i>the CYP3A5-6986A</i> &gt; <i>G allele 1</i> and acute rejection (<i>p</i>-value: 0.03, OR: 2.4). Consequently, the risk of acute graft rejection is higher for this group of pediatric recipients. Children with <i>CYP3A5-6986A</i> &gt; <i>G 1/3</i> polymorphism required a significantly higher tacrolimus dose to reach the target trough level and had a significantly lower tacrolimus CD ratio than <i>CYP3A5-6986A</i> &gt; <i>G 3</i> polymorphism, with <i>p</i>-values of 0.03 and 0.04, respectively. Regarding the CYP3A4gene, it was noticed that there was a higher frequency of <i>CYP3A4*1B-392A</i> &gt; <i>G (AA)</i> polymorphism in the AR group (33%, <i>n</i> = 10/30) and <i>CYP3A4*1B-392A</i> &gt; <i>G (GG)</i> polymorphism in the non-AR group (41%, <i>n</i> = 15/36), but the difference was not significant.</p> Conclusion <p>CYP3A gene polymorphism has an impact on the graft function and incidence of rejection, especially <i>CYP3A5-6986A</i> &gt; <i>G 1/3</i> 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.</p>

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

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  • 发表日期：

    2025年9月4日

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  • Fatina I. Fadel,
  • Doaa M. Salah,
  • Eman Gamal Elshabrawy,
  • Ali Sobh,
  • Yossef Mohamed Mossad,
  • Ashraf Abdelbaset Bakr,
  • Eman Abobakr Abd Alazem

摘要

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.