Pharmacogenomics of ADRs: Calcineurin Inhibitor Toxicity

描述（由申请人提供）：本资助提案的总体目标是确定影响肝移植患者钙调神经磷酸酶诱导的肾功能不全风险的遗传和人口统计学特征。钙调神经磷酸酶抑制剂（CNI），环孢素和他克莫司，是用于预防移植排斥反应的主要免疫抑制药物，但在治疗血液浓度下，它们可以在大约30-40%的患者中对肾脏造成不可逆的损伤。女性CNI肾功能不全的风险似乎高于男性。基于以下具体目标，我们将检验以下假设：移植后肾功能不全的个体风险在很大程度上取决于控制CNI在肾小管上皮细胞中的外排或代谢的基因（MDR 1和CYP 3AS）的遗传突变以及患者性别： 目标1。进行一项前瞻性研究，以确定肝移植患者肾功能不全的进展是否因MDR 1和CYP 3A 5基因型和患者性别而不同。 目标二。证明MDR 1 T2677和CYP 3AS *I基因的表达可增强CNI的细胞外排/代谢，并降低转染肾上皮细胞的细胞毒性，并且MDR 1 T2677和CYP 3A 5 *I基因产物的活性高于相应的MDRI G2677和CYP 3A 5 *3基因产物。 目标3。证明CNI的肾脏清除率以及CNI主要代谢产物的肾脏产生和清除率在MDR 1 TT 2677和CYP 3A 5 *I/*3基因型个体中分别增强。 我们还将检验以下假设，即影响CNI使用后肾功能不全的MDR 1突变也影响CNI摄取到介导移植物排斥的T淋巴细胞群中，并可能影响急性移植物排斥的风险。这将通过以下具体目标进行测试： 目标4。确定常见的MDR 1突变是否影响健康志愿者和肝移植患者的CD 4+和CD 8 + T淋巴细胞中Rhl 23和CNI的外排动力学。如果我们能够确定移植人群中CNI诱导的肾功能不全的遗传和人口统计学风险因素，这可能允许实施具有成本效益的前瞻性基因分型，以帮助个体化免疫抑制治疗。

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.