The overall objective of this project is to test the hypothesis that relationships between specific genetic? variants of drug metabolizing enzymes, drug transporters, drug targets and biological pathways are? associated with pharmacokinetics and adverse effects of immune suppressants, and clinical outcomes in? 5000 ethnically diverse kidney transplant recipients.
Aims I and II will determine the associations between? donor and recipient genetic variants of the glucuronosyltransferase (UGT) enzymes and drug transporters,? with mycophenolic acid (MPA) pharmacokinetics and mycophenolote mofetil (MMF) related toxicity.
For Aim ? I, known UGT enzyme and transporter variant genotypes will be assessed in recipient and donor DMA using? traditional low throughput genotyping methods. MPA pharmacokinetics will be measured in the recipient. In? Aim II, we will identify the variants associated with MMF adverse effects through a retrospective cohort? analysis (Test Cohort) using a high throughput customized single nucleotide polymorphism (SNP) Chip? followed by a prospective cohort (Validation Cohort) using low throughput genotyping methods. Given that? MPA is exclusively glucuronidated by UGT enzymes, that low MPA concentrations are associated with a? higher incidence of acute rejection, and high concentrations are associated with toxicity, identifying? individuals with variants leading to altered drug exposure could lead to individualized dosing and identify? patients at risk.
Aims III and IV will study the association of previously identified (from the literature) and new? genetic variants (identified from the SNPChip) of cytochrome P450 (CYP) 3A4/5 enzymes and drug? transporters with tacrolimus, cyclosporine and sirolimus pharmacokinetics and adverse effects. Current data? regarding the relationship of CYP and transporter variants with pharmacokinetics are conflicting and are too? weak for clinical prediction. Hence, other yet unidentified variants may be present. We will identify the? candidate variants associated with pharmacokinetics and adverse effects through a Test Cohort using the? SNPChip followed by validation in a prospective Validation Cohort using low throughput genotyping. Given? that there are significant ethnic differences in CYP 3A5 and transporter variant frequencies, the? pharmacokinetics will be evaluated in African Americans and Caucasians.
Aim V will determine the? association between genetic variants identified in Aims I-IV and clinical outcomes (acute rejection, and chronic? graft dysfunction). We expect the results of this project will help caregivers in the selection and dosing of? immunosuppressant therapies to minimize rejection episodes and foster better graft survival, to lower drug? toxicity, and to improve overall survival of transplant recipients.?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070119-03
Application #
7673670
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$360,472
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wu, Jennifer F; Muthusamy, Amutha; Al-Ghalith, Gabriel A et al. (2018) Urinary microbiome associated with chronic allograft dysfunction in kidney transplant recipients. Clin Transplant 32:e13436
Scheibner, Aileen; Remmel, Rory; Schladt, David et al. (2018) Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination. Pharmacotherapy :
Seibert, Stephan R; Schladt, David P; Wu, Baolin et al. (2018) Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients. Clin Transplant 32:e13424
Snoek, Rozemarijn; van Setten, Jessica; Keating, Brendan J et al. (2018) NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD. J Am Soc Nephrol 29:1772-1779
Oetting, William S; Wu, Baolin; Schladt, David P et al. (2018) Attempted validation of 44 reported SNPs associated with tacrolimus troughs in a cohort of kidney allograft recipients. Pharmacogenomics 19:175-184
Okour, Malek; Jacobson, Pamala A; Ahmed, Mariam A et al. (2018) Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure. J Clin Pharmacol 58:628-639
Dorr, Casey R; Wu, Baolin; Remmel, Rory P et al. (2018) Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing. Pharmacogenomics J :
Dorr, Casey R; Oetting, William S; Jacobson, Pamala A et al. (2018) Genetics of acute rejection after kidney transplantation. Transpl Int 31:263-277
Dorr, Casey R; Remmel, Rory P; Muthusamy, Amutha et al. (2017) CRISPR/Cas9 Genetic Modification of CYP3A5 *3 in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism. Drug Metab Dispos 45:957-965
Sanghavi, K; Brundage, R C; Miller, M B et al. (2017) Genotype-guided tacrolimus dosing in African-American kidney transplant recipients. Pharmacogenomics J 17:61-68

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