Pharmacogenetics of Immune Suppressants in Kidney Transplantation

University Of Minnesota, Minneapolis MN

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Abstract

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