William S Oetting1, Baolin Wu2, David P Schladt3, Weihua Guan2, Jessica van Setten4, Brendan J Keating5, David Iklé6, Rory P Remmel7, Casey R Dorr3,8, Roslyn B Mannon9, Arthur J Matas10, Ajay K Israni3,11,12, Pamala A Jacobson1. 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.
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.
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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