Genomics of Kidney Transplantation

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DESCRIPTION (provided by applicant): Our consortium consists of 7 centers which do a total of approximately 1000 kidney transplants/year; the consortium is now funded to study chronic graft dysfunction in kidney transplant recipients. Our funded grant provides support for establishing a multicenter database, and collecting data on donor and recipient demographics, kidney biopsy information, and recipient outcome. In the current application, we propose (using the infrastructure established) to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with similar immunosuppressive protocols. Our long-term goals are to determine whether it will be possible to individualize immunosuppressive therapy based on genetics in order to minimize rejection episodes, to lower drug toxicity, and improve long-term patient and graft survival. Our application consists of 2 Projects and 3 cores. Project by Israni (The Genetic Epidemiology of Deterioration of Kidney Alloqraft Function) has 2 specific aims: I) to study the relationships between allelic variants of transplant recipient genes (for cytokines, chemokines, fibrotic factors, thrombotic factors, growth factors, vascular cell adhesion molecules and hypertension) with chronic allograft dysfunction and estimated glomerular filtration rate (eGFR); II) to study the relationships between allelic variants of living donor genes with chronic allograft dysfunction and eGFR. We will also study the interaction of living donor and recipient genotypes on chronic allograft dysfunction and eGFR. Project by Jacobson (Pharmacogenetics of Immune Suppressants in Kidney Transplantation) has 5 specific Aims: Aims I and II will determine the relationships between donor and recipient genetic variants of the glucuronosyltransferase (UGT) enzymes and drug transporters, and mycophenolic acid (MPA) pharmacokinetics and mycophenolote mofetil (MMF) related toxicity. Aims III and IV will establish the association between previously identified and new genetic variants of CYP 3A4/5 enzymes and drug transporters on tacrolimus, cyclosporine and sirolimus systemic - concentrations and adverse effects. Aim \/ will determine the association between genetic variants identified in Aims I-IV and other variants such as drug targets and clinical outcomes. Three core units - an Administrative Core, a Clinical and Biostatistical Core and a Genotyping Core - will facilitate the proposed research.