We have an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year. We have developed a quality-controlled multicenter database with high quality data, and obtained DNA samples and clinical data on 962 recipients and 442 donors. Using our developed infrastructure, we propose to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that the genetic variation is associated with a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it is possible to individualize immunosuppressive therapy, based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity. Our application consists of 3 cores (Genetics Core, Clinical Core, and Administrative Core). We will do a genome wide association study (GWAS). Significant single nucleotide polymorphisms (SNPs) will be identified using the GWAS.Project 1 has 2 specific aims.<ul><li>Aim 1: To identify recipient SNPs that are associated with kidney allograft outcomes, including acute rejection, chronic graft dysfunction, and graft failure. </li><li>Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. </li></ul>Project 2 has 4 specific aims. <ul><li>Aim 1: To identify SNPs that are associated with tacrolimus blood levels.</li><li>Aim 2: To identify SNPs that are associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes.</li><li>Aim 3: To identify SNPs that are associated with mycophenolate-related toxicity. </li><li>Aim 4: To establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression of the pharmacologic targets of mycophenolate and calcineurin inhibitors. </li></ul>The projects use the genotyping data, which were provided by the Genetics Core, and clinical information, which were collected and entered into the multicenter database by the Clinical Core. Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both projects. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.Technical note: Regarding to the study design, all transplant recipients should be unrelated. Given the nature of transplantation, some donors may be related to recipients. The donor-recipient relationships are reported in the demographic file under the "related" column. As we did not collect full pedigree information for the related donor-recipient pairs, we have included a IBD file (calculated using PLINK) with the genotype data.

Genomics of Kidney Transplantation

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