Research Article

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

Department of Nephrology & Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, MN, USA

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William S Oetting

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

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Weihua Guan

Division of Biostatistics, School of Public Health, University of Minnesota, MN, USA

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Ajay K Israni

Department of Nephrology & Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, MN, USA

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Arthur J Matas

Division of Transplantation, Department of Surgery, University of Minnesota, MN, USA

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Rory P Remmel

Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, MN, USA

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Pamala A Jacobson

*Author for correspondence:

E-mail Address: jacob117@umn.edu

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

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for the DeKAF Investigators

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Published Online:12 Jun 2015https://doi.org/10.2217/pgs.15.42

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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 2015

Keywords:

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Vol. 16, No. 8

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History

Published online 12 June 2015

Published in print June 2015

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Keywords

DeKAF investigators

Arthur Matas, MD, Department of Surgery, University of Minnesota, Minneapolis, MN, USA, E-mail: matas001@umn.edu; J Michael Cecka, MD, UCLA Immunogenetics Center, Los Angeles, CA, USA, E-mail: mcecka@ucla.edu; John Connett, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA, E-mail: john-c@biostat.umn.edu; Fernando G Cosio, MD, Division of Nephrology, Mayo Clinic, Rochester, MN, USA, E-mail: Cosio.Fernando@mayo.edu; Robert Gaston, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, USA, E-mail: rgaston@uab.edu; Rosalyn Mannon, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, USA, E-mail: rmannon@uab.edu; Sita Gourishankar, MD, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada, E-mail: sitag@ualberta.ca; Joseph P Grande, MD, PhD, Mayo Clinic College of Medicine, Rochester, MN, USA, E-mail: Grande.Joseph@mayo.edu; Lawrence Hunsicker, MD, Nephrology Division, Iowa City, IA, USA, E-mail: lawrencehunsicker@uiowa.edu; Bertram Kasiske, MD, Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN, USA, E-mail: kasis001@umn.edu; and David Rush, MD, Health Sciences Center, Winnipeg MB, Canada, E-mail: drush@exchange.hsc.mb.ca.

Participating centers

Participating transplant centers were University of Alberta, Edmonton, Canada; University of Manitoba, Winnipeg, Canada; University of Minnesota, Minneapolis, MN, USA; Hennepin County Medical Center, Minneapolis, MN, USA; Mayo Clinic, Rochester, MN, USA; University of Iowa, Iowa City, IA, USA and University of Alabama, Birmingham, AL, USA.

Acknowledgements

The authors thank the dedication and hard work of their coordinators: University of Alberta: N Bobocea, T Wong, A Geambasu and A Sader; University of Manitoba: M Ross and K Peters; University of Minnesota: M DeGrote and R Brown; Hennepin County Medical Center: L Berndt; Mayo Clinic: T DeLeeuw; University of Iowa: W Wallace and T Lowe; University of Alabama: T Hailey. The authors also thank the research scientists for dedicated work: M Brott and A Muthusamy.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Disease or the NIH.

Financial & competing interests disclosure

This project was supported by grant number (5U19-AI070119 and 5U01-AI058013) from the National Institute of Allergy and Infectious Disease. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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Multigene predictors of tacrolimus exposure in kidney transplant recipients

Abstract

References