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Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies

Oetting, William S., PhD1; Wu, Baolin, PhD2; Schladt, David P., MS3; Guan, Weihua, PhD2; van Setten, Jessica, PhD4; Keating, Brendan J., DPhil5; Iklé, David, PhD6; Remmel, Rory P., PhD7; Dorr, Casey R., PhD3,8; Mannon, Roslyn B., MD9; Matas, Arthur J., MD10; Israni, Ajay K., MD, MS3,11,12; Jacobson, Pamala A., PharmD1 for the DeKAF Genomics and GEN-03 Investigators

doi: 10.1097/TP.0000000000002625
Original Basic Science—General
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Background. The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.

Methods. We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients—a discovery cohort and a confirmation cohort—to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.

Results. Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.

Conclusions. These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

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

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

3 Hennepin Healthcare Research Institute, Minneapolis, MN.

4 Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

5 Penn Transplant Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA.

6 Rho, Chapel Hill, NC.

7 Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN.

8 Department of Medicine, University of Minnesota, Minneapolis, MN.

9 Division of Nephrology, University of Alabama, Birmingham, AL.

10 Department of Surgery, University of Minnesota, Minneapolis, MN.

11 Department of Nephrology, Hennepin Healthcare, Minneapolis, MN.

12 Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN.

Received 12 October 2018. Revision received 20 December 2018.

Accepted 1 January 2019.

W.S.O., B.W., D.P.S., W.G., A.K.I., P.A.J., D.I., and R.B.M. received support for this project from the National Institutes of Health NIAID Genomics of Transplantation (grant 5U19AI070119). A.J.M. received support for this project from the National Institutes of Health Genomics of Transplantation (grant 5U19-AI070119), ARRA supplement (grant 5U19-AI070119), and DeKAF (grant 5U01-AI058013). J.v.S., B.J.K., R.P.R., and C.R.D. received no support.

The authors declare no conflicts of interest.

W.S.O., B.W., D.P.S., W.G., J.v.S., B.J.K., A.K.I., and P.A.J. participated in research design, writing of the paper, performance of the research, and data analysis. D.I. participated in research design and performance of the research. R.P.R. participated in research design, performance of the research, and writing of the paper. C.R.D. participated in writing of the paper, performance of the research, and data analysis. R.B.M. and A.J.M. participated in research design and writing of the paper.

* DeKAF Genomics and GEN-03 Investigators: Arthur Matas, MD, Department of Surgery, University of Minnesota, Minneapolis, MN (matas001@umn.edu); J. Michael Cecka, MD, UCLA Immunogenetics Center, Los Angeles, CA (mcecka@ucla.edu); John Connett, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN (john-c@biostat.umn.edu); Fernando G. Cosio, MD, Division of Nephrology, Mayo Clinic, Rochester, MN (Cosio.Fernando@mayo.edu); Robert Gaston, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL (rgaston@uab.edu); Rosalyn Mannon, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL (rmannon@uabmc.edu); Sita Gourishankar, MD, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada, (sitag@ualberta.ca); Joseph P. Grande, MD, PhD, Mayo Clinic College of Medicine, Rochester, MN (Grande.Joseph@mayo.edu); Lawrence Hunsicker, MD, Nephrology Division, Iowa City, IA (lawrencehunsicker@uiowa.edu); Bertram Kasiske, MD, Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN (kasis001@umn.edu); and David Rush, MD, Health Sciences Center, Winnipeg, MB, Canada (drush@exchange.hsc.mb.ca).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: William S. Oetting, PhD, Department of Experimental and Clinical Pharmacology, College of Pharmacy, 7-115 Weaver-Densford Hall, 308 Harvard St SE, University of Minnesota, Minneapolis, MN 55455. (oetti001@umn.edu).

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