title: Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients.
abstract: BACKGROUND
  This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac).
  
  
  METHODS
  Allelic discrimination assays were used for genotyping. Multivariate time-dependent Cox proportional hazard models, multiple linear regression using the generalized estimating equation and linear mixed-effect models were used for statistical analysis.
  
  
  RESULTS
  Expression of CYP3A5 by either or both the donor and the recipient was significantly associated with lower Tac, but not CsA, dose-normalized trough levels. In the whole population, graft loss was only significantly associated with longer exposure to high calcineurin inhibitor (CNI) concentrations (hazard ratio, 6.93; 95% confidence interval, 2.13-22.55), P = 0.00129), whereas in the Tac subgroup, the risk of graft loss was significantly higher in recipient CYP3A5*1 expressers (hazard ratio, 3.39; 95% confidence interval, 1.52-7.58; P = 0.0028). Renal function was significantly associated with: (1) baseline modification of diet in renal disease (β = 0.51 ± 0.05; P < 0.0001); (2) duration of patient follow-up (per visit, β = -0.98 ± 0.22; P < 0.0001); and (3) CNI exposure (per quantile increase, β = -2.42 ± 0.59; P < 0.0001). No genetic factor was associated with patient survival, acute rejection, liver function test results, recurrence of viral or other initial liver disease, or renal function.
  
  
  CONCLUSIONS
  This study confirms the effect of CYP3A5*3 on tacrolimus dose requirement in liver transplantation and shows unexpected associations between the type of, and exposure to, CNI and either chronic rejection or graft loss. None of the genetic polymorphisms studied had a noticeable impact on renal function degradation at 10 years.
authors.affiliation: 1 Department of Hepatology, CHU Limoges, France.2 UMR 850 INSERM, Univ Limoges, France.3 Department of Pharmacology and Toxicology, CHU Limoges, France.4 AP-HP, Hôpital Paul Brousse, Laboratoire d'Anatomie Pathologique, Villejuif, France.5 AP-HP, Hôpital Paul Brousse, Centre Hépato-biliaire, Villejuif, France.6 UMR 1193 INSERM, Univ Paris-Sud, Villejuif, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Debette-Gratien
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Woillard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Mylène
authors.initials: M
authors.lastname: Sebagh
authors.forename: Véronique
authors.initials: V
authors.lastname: Loustaud-Ratti
authors.forename: Denis
authors.initials: D
authors.lastname: Sautereau
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet