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

Janet K. Coller, Jeyamani Ramachandran, Libby John, Jonathan Tuke, Alan Wigg, Matthew Doogue

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (Css) 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 Css 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 Css. At 3 months post-transplant modelling revealed an association between tacrolimus Css and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% Css variance. Jonckheere–Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, Css decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus Css, further validation in larger cohorts is required.

Original languageEnglish
Pages (from-to)2170-2175
Number of pages6
JournalBritish Journal of Clinical Pharmacology
Volume85
Issue number9
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Keywords

  • cytochrome P450 enzymes
  • drug transporters
  • genetics
  • pharmacokinetics
  • transplantation

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