Pharmacogenetics of Immune Suppressants in Kidney Transplantation

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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.