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

DeKAF Genomics and GEN-03 Investigators

Research output: Contribution to journalArticle

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

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Genome-Wide Association Study
Tacrolimus
Immunosuppressive Agents
Genomics
Pharmacokinetics
Transplantation
Leukopenia
Organ Transplantation
Single Nucleotide Polymorphism
Allografts
Anemia
Phenotype
Kidney

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Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies. / DeKAF Genomics and GEN-03 Investigators.

In: Transplantation, Vol. 103, No. 6, 01.06.2019, p. 1131-1139.

Research output: Contribution to journalArticle

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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.",
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AU - Oetting, William S

AU - Wu, Baolin

AU - Schladt, David P.

AU - Guan, Weihua

AU - van Setten, Jessica

AU - Keating, Brendan J.

AU - Iklé, David

AU - Remmel, Rory P

AU - Dorr, Casey R.

AU - Mannon, Roslyn B.

AU - Matas, Arthur J.

AU - Israni, Ajay K.

AU - Jacobson, Pamala A

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