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.
|Dorr, Casey R; Remmel, Rory P; Muthusamy, Amutha et al. (2017) CRISPR/Cas9 Genetic Modification of CYP3A5 *3 in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism. Drug Metab Dispos 45:957-965|
|Oetting, William S; Dorr, Casey; Remmel, Rory P et al. (2017) Concepts of Genomics in Kidney Transplantation. Curr Transplant Rep 4:116-123|
|Oetting, W S; Jacobson, P A; Israni, A K (2017) Validation Is Critical for Genome-Wide Association Study-Based Associations. Am J Transplant 17:318-319|
|Sanghavi, K; Brundage, R C; Miller, M B et al. (2017) Genotype-guided tacrolimus dosing in African-American kidney transplant recipients. Pharmacogenomics J 17:61-68|
|Dorr, Casey R; Freedman, Barry I; Hicks, Pamela J et al. (2016) Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes. PLoS One 11:e0152775|
|Oetting, W S; Schladt, D P; Guan, W et al. (2016) Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. Am J Transplant 16:574-82|
|Julian, B A; Gaston, R S; Brown, W M et al. (2016) Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index. Am J Transplant :|
|Freedman, Barry I; Pastan, Stephen O; Israni, Ajay K et al. (2016) APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors. Transplantation 100:194-202|
|Freedman, B I; Julian, B A; Pastan, S O et al. (2015) Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant 15:1615-22|
|Ong, Song; Mannon, Roslyn B (2015) Genomic and proteomic fingerprints of acute rejection in peripheral blood and urine. Transplant Rev (Orlando) 29:60-7|
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