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Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients

The Pharmacogenomics Journal volume 18, pages 501–505 (2018)Cite this article

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Abstract

The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.

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Acknowledgements

We thank the research subjects for their participation in this study. We acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers and Danielle Berglund; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientists Marcia Brott and Amutha Muthusamy. This study was supported in part by the NIH/NIAID Grants 5U19-AI070119 and 5U01-AI058013.

Author information

Author notes

  1. W S Oetting, B Wu, D P Schladt, W Guan, R P Remmel, R B Mannon, A J Matas, A K Israni and P A Jacobson: The members of DeKAF Genomics Investigators are listed above the References.

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

    W S Oetting & P A Jacobson

  2. Department of Biostatistics, University of Minnesota, Minneapolis, MN, USA

    B Wu & W Guan

  3. Minneapolis Medical Research Foundation, Minneapolis, MN, USA

    D P Schladt & A K Israni

  4. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA

    R P Remmel

  5. Division of Nephrology, University of Alabama, Birmingham, AL, USA

    R B Mannon

  6. Minneapolis, Department of Surgery, University of Minnesota, MN, USA

    A J Matas

  7. Minneapolis, Department of Medicine, Hennepin County Medical Center, MN, USA

    A K Israni

  8. Department of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA

    A K Israni

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Oetting, W., Wu, B., Schladt, D. et al. Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients. Pharmacogenomics J 18, 501–505 (2018). https://doi.org/10.1038/tpj.2017.49

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