The major goal of this proposal is to determine if common polymorphic alleles in biologically relevant genes, in either the recipient or the donor genome, influence kidney transplant outcome. We hypothesize that individuals have a genetic predisposition to the likelihood of rejection or drug toxicity that will, in part, determine organ transplant outcome. This genetic predisposition may come from multiple gene polymorphisms in the same individual. To test this hypothesis, we will analyze the DNA from patients enrolled in a three-arm study analyzing the effects of different immunosuppressant regimens, Cyclosporine/MMF, high Tacrolimus/low Sirolimus levels and low Tacrolimus/high Sirolimus levels. This will allow us test different gene polymorphisms in populations of individuals taking identical immunosuppressant regimens for three different immunosuppressive protocols.
The specific aims of the application are as follows: 1. To analyze polymorphisms in candidate genes of both recipients and donors to determine if specific alleles alter the outcome of solid organ transplantation. 2. To determine the effects of gene polymorphisms on different immunosuppressive drug regimens. 3. To develop a statistical approach to analyze multiple gene interactions in transplant outcome. The ability to predict the likelihood of a clinical event like acute or chronic rejection, or toxicity from a specific drug, could greatly aid success for an organ transplant recipient. Understanding the impact of specific alleles of either an individual gene or sets of multiple polymorphisms, in both recipient and donor genomes, will be important in defining high and low risk individuals. Immunosuppressive regimens have been designed to do the most good (minimize rejection) while doing the least harm (minimize toxicity). But, to date, most transplant programs use mostly the same immunosuppressive regimes for most recipients at their center. Only a few clinical parameters are used to alter immunosuppressive protocols. If we show that specific gene polymorphisms are associated with significantly increased incidence of rejection, we can design clinical trials to randomize transplant recipients with these polymorphisms to different immunosuppressive regimes designed to reduce their rejection incidence. Similarly, if we show that specific gene polymorphisms are associated with a significant increase rate of chronic graft rejection (with or without an antecedent rejection episode), we can design clinical trials to randomize recipients as to their gene polymorphisms to regimens designed to reduce the incidence of chronic dysfunction.
| International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) (2015) Design and Implementation of the International Genetics and Translational Research in Transplantation Network. Transplantation 99:2401-12 |
| Oetting, William S; Guan, Weihua; Schladt, David P et al. (2012) Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients. Liver Transpl 18:1399-405 |
| Oetting, William S; Zhu, Yanni; Brott, Marcia J et al. (2012) Validation of genetic variants associated with early acute rejection in kidney allograft transplantation. Clin Transplant 26:418-23 |
