The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (C_ss) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and C_ss and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere–Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on C_ss. At 3 months post-transplant modelling revealed an association between tacrolimus C_ss and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% C_ss variance. Jonckheere–Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, C_ss decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus C_ss, further validation in larger cohorts is required.