Multigene predictors of tacrolimus exposure in kidney transplant recipients

Rebecca A. Pulk, David S. Schladt, William S. Oetting, Weihua Guan, Ajay K. Israni, Arthur J. Matas, Rory P. Remmel, Pamala A. Jacobson

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Aim: Determine the effect of the genetic variants beyond CYP3A5∗3 on tacrolimus disposition. Patients & methods: We studied genetic correlates of tacrolimus trough concentrations with POR∗28, CYP3A4∗22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). Results: Subjects carrying one or more CYP3A5∗1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10-75). The presence of one or two POR∗28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5∗1 and clinical factors (p = 0.037). In subset analyses, POR∗28 was significant only in CYP3A5∗3/∗3 carriers (p = 0.03). The CYP3A4∗22 variant and the ABBC2 haplotypes were not associated. Conclusion: This study confirmed that CYP3A5∗1 was associated with lower tacrolimus trough concentrations. POR∗28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4∗22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 201.

Original languageEnglish (US)
Pages (from-to)841-854
Number of pages14
JournalPharmacogenomics
Volume16
Issue number8
DOIs
StatePublished - Jul 1 2015

Keywords

  • ABCC2
  • POR
  • calcineurin inhibitor
  • cytochrome P450 3A4 and 3A5
  • kidney transplant
  • pharmacogenomics
  • pharmacokinetics
  • tacrolimus

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