Pharmacogenomics of ADRs: Calcineurin Inhibitor Toxicity

描述（由申请人提供）：本拨款提案的总体目标是确定影响肝移植患者钙调磷酸酶诱导肾功能障碍风险的遗传和人口统计学特征。钙调磷酸酶抑制剂（CNIs），环孢素和他克莫司，是用于预防移植物排斥反应的主要免疫抑制药物，但在治疗血药浓度下，它们会对大约30-40%的患者的肾脏造成不可逆的损害。女性患CNI肾功能障碍的风险似乎高于男性。基于以下具体目的，我们将检验移植后肾功能障碍的个体风险在很大程度上取决于控制肾小管上皮细胞CNIs外排或代谢的基因（MDR1和CYP3AS）的遗传突变以及患者性别的假设：

DESCRIPTION (provided by applicant): The overall objective of this grant proposal is to identify genetic and demographic traits that affect the risk of calcineurin-induced renal dysfunction in liver transplantation patients. Calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are mainstay immunosuppressive drugs used to prevent graft rejection, but at therapeutic blood concentrations, they can cause irreversible damage to the kidney in approximately 30-40% of patients. The risk of CNI renal dysfunction appears to be greater for females than males. With the following specific aims, we will test the hypothesis that individual risk for post-transplantation renal dysfunction is determined in significant part by inherited mutations in genes (MDR1 and CYP3AS) that control the efflux or metabolism of CNIs in renal tubular epithelial cells, and by patient gender: Aim 1. Conduct a prospective study to determine whether the progression of renal dysfunction in liver transplantation patients differs as a function of MDR1 and CYP3A5 genotypes and patient gender. Aim 2. Demonstrate that expression of the MDR1 T2677 and CYP3AS*I genes enhance cellular efflux/metabolism of CNIs and reduce cytotoxicity in transfected renal epithelial cells, and that the MDR1 T2677 and CYP3A5*I gene products are more active than respective MDRI G2677 and CYP3A5*3 gene products. Aim 3. Demonstrate that the renal clearance of CNIs and renal production and clearance of primary CNI metabolites is enhanced for individuals with the MDR1 TT2677 and CYP3A5*I/*3 genotypes, respectively. We will also test the hypothesis that the MDR1 mutations that affect renal dysfunction following CNI use, also influence the uptake of CNIs into T-lymphocyte cell populations that mediate graft rejection, and potentially affect the risk of acute graft rejection. This will be tested with the following Specific Aim: Aim 4. Determine whether common MDR1 mutations affect the efflux kinetics of Rhl23 and the CNIs in CD4+ and CD8+ T-lymphocytes from healthy volunteers and liver transplantation patients. If we can identify genetic and demographic risk factors for CNI-induced renal dysfunction in the transplantation population, this may permit the implementation of cost-effective, prospective genotyping to aid in individualizing immunosuppressive therapy.