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

Transplantation
William S OettingDeKAF Genomics and GEN-03 Investigators

Abstract

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. 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. 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. 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.

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Citations

Dec 10, 2019·Current Opinion in Organ Transplantation·Francesca Zanoni, Krzysztof Kiryluk
Jul 15, 2020·Journal of Clinical Pharmacy and Therapeutics·Tam T NguyenPamala A Jacobson
Nov 7, 2020·Pharmacotherapy·Angela Q MaldonadoChristin Rogers
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Jun 22, 2021·Clinical Pharmacology and Therapeutics·Ayesha MuhammadSara L Van Driest
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Mar 4, 2021·Transplantation·Jihoon G YoonUNKNOWN the Korean Organ Transplantation Registry (KOTRY) study group

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