Genetic variants associated with immunosuppressant pharmacokinetics and adverse effects in the DeKAF genomics genome-wide association studies

William S. Oetting, Baolin Wu, David P. Schladt, Weihua Guan, Jessica Van Setten, Brendan J. Keating, David Iklé, Rory P. Remmel, Casey R. Dorr, Roslyn B. Mannon, Arthur J. Matas, Ajay K. Israni, Pamala A. Jacobson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1131-1139
Number of pages9
JournalTransplantation
Volume103
Issue number6
DOIs
StatePublished - Jun 1 2019

Bibliographical note

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

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© 2019 Wolters Kluwer Health, Inc. All rights reserved.

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