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

doi:10.2217/pgs.15.42

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 journal › Article › peer-review

34 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 language	English (US)
Pages (from-to)	841-854
Number of pages	14
Journal	Pharmacogenomics
Volume	16
Issue number	8
DOIs	https://doi.org/10.2217/pgs.15.42
State	Published - Jul 1 2015
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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10.2217/pgs.15.42

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title = "Multigene predictors of tacrolimus exposure in kidney transplant recipients",

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.",

keywords = "ABCC2, calcineurin inhibitor, cytochrome P450 3A4 and 3A5, kidney transplant, pharmacogenomics, pharmacokinetics, POR, tacrolimus",

author = "Pulk, {Rebecca A.} and Schladt, {David S.} and Oetting, {William S.} and Weihua Guan and Israni, {Ajay K.} and Matas, {Arthur J.} and Remmel, {Rory P.} and Jacobson, {Pamala A.}",

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doi = "10.2217/pgs.15.42",

language = "English (US)",

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T1 - Multigene predictors of tacrolimus exposure in kidney transplant recipients

AU - Pulk, Rebecca A.

AU - Schladt, David S.

AU - Oetting, William S.

AU - Guan, Weihua

AU - Israni, Ajay K.

AU - Matas, Arthur J.

AU - Remmel, Rory P.

AU - Jacobson, Pamala A.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

KW - ABCC2

KW - calcineurin inhibitor

KW - cytochrome P450 3A4 and 3A5

KW - kidney transplant

KW - pharmacogenomics

KW - pharmacokinetics

KW - POR

KW - tacrolimus

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Multigene predictors of tacrolimus exposure in kidney transplant recipients

Abstract

Keywords

ASJC Scopus subject areas

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