CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6±3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29–0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

[1]  M. V. van Dieijen-Visser,et al.  Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients. , 2006, Pharmacogenomics.

[2]  D. Min,et al.  Association of the CYP3A4*1B 5´-Flanking Region Polymorphism With Cyclosporine Pharmacokinetics in Healthy Subjects , 2003, Therapeutic drug monitoring.

[3]  L. Wojnowski,et al.  Clinical implications of CYP3A polymorphisms , 2006, Expert opinion on drug metabolism & toxicology.

[4]  Guang-Ji Wang,et al.  Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients , 2006, Acta Pharmacologica Sinica.

[5]  P. Watkins,et al.  CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. , 2003, Journal of applied physiology.

[6]  M. Ingelman-Sundberg,et al.  Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. , 2005, Biochemical and biophysical research communications.

[7]  B. Ring,et al.  Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[8]  R. Calne Cyclosporine as a milestone in immunosuppression. , 2004, Transplantation proceedings.

[9]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[10]  J. Squifflet,et al.  The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. , 2004, Pharmacogenetics.

[11]  J. Vandenbroucke,et al.  ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis. , 2005, Kidney international.

[12]  Zhaoqian Liu,et al.  EFFECTS OF GENETIC POLYMORPHISMS OF CYP3A4, CYP3A5 AND MDR1 ON CYCLOSPORINE PHARMACOKINETICS AFTER RENAL TRANSPLANTATION , 2006, Clinical and experimental pharmacology & physiology.

[13]  S. Wrighton,et al.  Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). , 1990, Molecular pharmacology.

[14]  L. Wojnowski Genetics of the variable expression of CYP3A in humans. , 2004, Therapeutic drug monitoring.

[15]  W. Weimar,et al.  Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR‐1, CYP3A4, and CYP3A5 genes , 2004, Clinical pharmacology and therapeutics.

[16]  V. Haufroid,et al.  CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  H. Ackermann,et al.  ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. , 2005, Journal of the American Society of Nephrology : JASN.

[18]  K. Thummel A genetic test for immunosuppressant dose selection? , 2004, Pharmacogenetics.

[19]  W. Weimar,et al.  Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus , 2003, Clinical pharmacology and therapeutics.

[20]  Gerd Offermann,et al.  The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients. , 2004, Pharmacogenetics.

[21]  Yang Dai,et al.  In vitro metabolism of cyclosporine A by human kidney CYP3A5. , 2004, Biochemical pharmacology.

[22]  M. Eichelbaum,et al.  CYP3A genetics in drug metabolism , 2001, Nature Medicine.

[23]  E. Schuetz,et al.  Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. , 2002, Molecular pharmacology.

[24]  P. Watkins,et al.  Bimodal distribution of renal cytochrome P450 3A activity in humans. , 1996, Molecular pharmacology.

[25]  M. Ingelman-Sundberg,et al.  CYP3A7 protein expression is high in a fraction of adult human livers and partially associated with the CYP3A7*1C allele , 2005, Pharmacogenetics and genomics.

[26]  B. Roe,et al.  Sequence diversity and haplotype structure at the human CYP3A cluster , 2006, The Pharmacogenomics Journal.

[27]  N Risch,et al.  High-throughput genotyping with single nucleotide polymorphisms. , 2001, Genome research.

[28]  U. Christians,et al.  Alternative cyclosporine metabolic pathways and toxicity. , 1995, Clinical biochemistry.

[29]  G. Kearns,et al.  Cytochrome P450 3A , 1999, Clinical pharmacokinetics.

[30]  U. Kunzendorf,et al.  CYP3A5 Genotype Markedly Influences the Pharmacokinetics of Tacrolimus and Sirolimus in Kidney Transplant Recipients , 2007, Clinical pharmacology and therapeutics.