Pharmacogenomics of ADRs: Calcineurin Inhibitor Toxicity

描述(由申请人提供)：这项赠款提案的总体目标是确定影响肝移植患者钙调神经磷酸酶所致肾功能障碍风险的遗传和人口学特征。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，但在治疗性血药浓度下，它们可对大约30%-40%的患者造成不可逆转的肾脏损害。女性患CNI肾功能障碍的风险似乎比男性大。出于以下特定目的，我们将检验以下假设：移植后肾功能障碍的个体风险在很大程度上是由控制肾小管上皮细胞CNI外流或代谢的基因(MDR1和CYP3AS)的遗传突变以及患者性别决定的： 目的1.进行一项前瞻性研究，以确定肝移植患者肾功能障碍的进展是否与mdr1和CYP3A5基因型别和患者性别有关。 目的2.证实MDR1T2677和CYP3AS*I基因的表达增强了CNI的细胞外排/代谢，降低了对肾上皮细胞的细胞毒性，并且MDR1T2677和CYP3A5*I基因产物比各自的MDRI G2677和CYP3A5*3基因产物更具活性。 目的3.证实携带MDR1TT2677和CYP3A5*I/*3基因的个体肾脏对CNI的清除量和主要CNI代谢物的生成和清除量分别增加。 我们还将测试这样一种假设，即使用CNI后影响肾功能障碍的MDR1突变也会影响CNI对介导移植排斥反应的T淋巴细胞群体的摄取，并可能影响移植急性排斥反应的风险。这将以以下具体目标进行测试： 目的4.确定常见的mdr1基因突变是否影响健康志愿者和肝移植患者的CD4+和CD8+T淋巴细胞中Rh123和CNI的外流动力学。如果我们能在移植人群中识别CNI所致肾功能障碍的遗传和人口学危险因素，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.