We propose to investigate the pharmacogenomics ofthe calcineurin inhibitors (CNI) and mycophenolate in kidney transplantation. Despite the tremendous therapeutic advances that these drugs have provided, their use is still limited by toxicities and therapy failures. Unfortunately, we are unable to discern which patients will develop toxicity or fail therapy. For these patients the consequences can be severe including return to dialysis, retransplantation and death. Monitoring of blood levels has improved our ability to improve and tailor therapy once immune suppression is initiated; however, initial doses are largely empiric and use the crude one size fits all approach. This results in subtherapeutic and supratherapeutic levels in a substantial number of patients. There are also a substantial number oif patients who despite achieving therapeutic levels will fail therapy and develop toxicity. We will address major therapy limitations - toxicity and failure - through this application. Genetic variation may be an important factor in predicting who will develop toxicity or fail therapy. We will conduct a genome wide association study in 3000 kidney transplant recipients to define single nucleotide polymorphisms (SNPs) associated with tacrolimus blood levels, and calcineurin inhibitor (CNI) related nephrotoxicity, immune suppressant related new onset diabetes after transplant (NODAT), and mycophenolate related leukopenia and anemia. The findings will then be validated in 3000 additional kidney transplant recipients. We will also study, in a subset of 600 recipients, the relationships between SNPs of the pharmacologic targets, CN and inosine monophosphatase dehydrogenase (IMPDH), mRNA expression of these targets, their protein activity in PBMCs and rejection and toxicities. Our goal is to develop clinical dosing models for the CNIs using clinical factors and SNPs such that we can individualize dosing and to identify genetic factors associated with CNI or mycophenolate toxicities such that regimens may be individually tailored to avoid or minimize the risk agent(s). The long term goal is to provide every patient the dose appropriate for them and the immunosuppressive regimen with the lowest toxicity risk and highest success. SNPs identified in this project will then be combined with important SNPs identified as important towards acute rejection, chronic graft dysfunction and graft failure in project 1.
Immunosuppressive drugs are associated with substantial toxicities and some patients fail therapy. Genetic factors may be associated with these events. Pretransplant testing for these factors will allow for the tailoring of regimens to the individual with the greatest chance of success.
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|Dorr, Casey R; Oetting, William S; Jacobson, Pamala A et al. (2018) Genetics of acute rejection after kidney transplantation. Transpl Int 31:263-277|
|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|
|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|
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