This grant application is a response to RFA-AI-10-019. We have a) an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year;b) developed a quality-controlled multicenter database with high quality data, and as ofthis writing c) obtained DNA samples and clinical data on 2865 recipients and 1010 donors. We propose (using our developed infrastructure) to study whether genetic variants are, in part, responsible forthe differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that 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 will be 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 2 Proiects and 3 Cores. We will do a genome wide association study (GWAS) using a test and validation cohort design. Significant SNPs will be identified using the GWAS in a test cohort (of 3000 recipients and 1000 donors). Important SNPs will then be validated in analyses of samples from 3000 recipients and 1300 donors enrolled throughout this renewal. Project 1 will study SNPs that are associated with graft outcome and has 2 Specific Aims ? Aim 1: To identify recipient single nucleotide polymorphisms (SNPs) that are associated with kidney allograft outcomes (acute rejection, chronic graft dysfunction and graft failure).
Aim 2 : To identify living donor SNPs that are associated with kidney allograft outcomes. Proiect 2. has 4 Specific Aims.
Aim 1 : To identify SNPs associated with tacrolimus blood levels;
Aim 2 : to identify SNPs associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes;
Aim 3; to identify SNPs associated with mycophenolate-related toxicity.
Our Aim 4 : is to establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression ofthe pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects are highly interrelated and the 3 Cores support both Projects. The Projects use the same DNA and genotyping data (provided by the Genetics Core), and clinical information (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. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.
Identification of SNPs associated with graft outcome and/or drug disposition or toxicity may lead to individualization of immunosuppressive therapy, based on genetics, to improve recipient outcomes (minimize rejection, graft dysfunction and failure, and drug toxicity). At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug-specific toxicity.
|Oetting, William S; Guan, Weihua; Schladt, David P et al. (2014) Telomere length of recipients and living kidney donors and chronic graft dysfunction in kidney transplants. Transplantation 97:325-9|
|Claes, Kathleen J; Heye, Sam; Bammens, Bert et al. (2013) Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients. Transpl Int 26:973-81|
|Israni, Ajay K; Leduc, Robert; Jacobson, Pamala A et al. (2013) Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype. Clin Transplant 27:348-58|
|Israni, Ajay K; Riad, Samy M; Leduc, Robert et al. (2013) Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics. Transpl Int 26:982-9|
|Jacobson, Pamala A; Schladt, David; Israni, Ajay et al. (2012) Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium. Transplantation 93:624-31|
|Jacobson, Pamala A; Schladt, David; Oetting, William S et al. (2011) Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation 91:309-16|
|Jacobson, Pamala A; Oetting, William S; Brearley, Ann M et al. (2011) Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91:300-8|
|Oetting, William S; Schladt, David P; Leduc, Robert E et al. (2011) Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort. Transpl Int 24:1231-8|
|Passey, Chaitali; Birnbaum, Angela K; Brundage, Richard C et al. (2011) Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol 72:948-57|
|Mannon, Roslyn B (2010) Immune monitoring and biomarkers to predict chronic allograft dysfunction. Kidney Int Suppl :S59-65|
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