Liver transplantation is a life-saving technique for patients with end-stage liver disease. Pharmacogenetics is promising to explain a part of variability of calcineurin inhibitors efficacy and toxicity. The goal of this study was to investigate the influence of polymorphisms in the CYP3A enzymes and ABCB1 membrane transporter from both donors and recipients on clinical outcomes and renal function in adult liver transplant patients on cyclosporine (CsA) or tacrolimus (Tac).

Methods: Data from 170 recipients over 10 years post-transplantation were investigated. The recipient and donor CYP3A4*22, CYP3A5*3 and ABCB1 exons 26, 12 and 21 polymorphisms were genotyped. Multivariate time-dependent Cox proportional hazard and multiple linear regressions using the generalized estimating equation (gee) were used for statistical analysis.

Results: A higher risk of graft loss was significantly associated with the recipient CYP3A5 expressor genotype (HR=2.53; 95%CI (1.17-5.46); p=0.01870), recurrence of initial liver disease (HR=2.29; 95%CI (1.19-4.43); p=0.01315) and percent time spent in the high quantile of exposure to calcineurin inhibitors CNI (HR=8.36; 95%CI (2.54-27.50); p=0.00047). A higher risk of chronic graft rejection was found in the recipient ABCB1 exon 12 CC genotype (exon 12 CC vs. TT, HR=3.12; 95%CI (1.35-7.24); p=0.0078) adjusted on the CNI received (Tac vs. CsA HR=3.22; 95%CI (1.57-6.60); p=0.0015). The overall CNI exposure calculated using exposure quantiles at each visit and expressed as high, middle or low (per quantile increase, β±SD =-2.41 ± 0.59; p<0.0001), recipient age (per year increase, β±SD =-0.37 ± 0.14; p=0.0084), baseline MDRD (per unit decrease, β=-0.51 ± 0.05; p<0.0001) and duration of patient follow-up (per visit, β=-0.98 ± 0.22; p<0.0001) were significantly associated with renal function degradation. No genetic factor was associated with patient survival, acute rejection, liver function test, viral or other initial liver disease recurrence, or nephrotoxicity.

Conclusion: CYP3A5 and ABCB1 genotypes of recipients may help to monitor patients after liver transplantation.

CITATION INFORMATION: Debette-Gratien M, Woillard J, Picard N, Sebbagh M, Sautereau D, Loustaud-Ratti V, Samuel D, Marquet P. Influence of Donor and Recipient CYP3A4, CYP3A5 and ABCB1 Genotypes on Outcomes in Liver Transplants. Am J Transplant. 2016;16 (suppl 3).

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