Pharmacogenetics of Immune Suppressants in Kidney Transplantation

这个项目的总体目标是测试假设，特定基因之间的关系 药物代谢酶、药物转运体、药物靶标和生物途径的变体有 与免疫抑制剂的药代动力学和不良反应相关，以及临床结果 5000名不同种族的肾移植受者。AIMS I和AIMS II将确定 供体和受体葡萄糖醛酸基转移酶(UGT)酶和药物转运体的遗传变异， 与霉酚酸(MPA)的药代动力学和霉酚酸酯(MMF)相关的毒性。为了达到目标 I，已知的UGT酶和转运体变异基因型将在受体和供体DMA中进行评估 传统的低通量基因分型方法。将在受者体内测量甲孕酮的药代动力学。在……里面 目的II，我们将通过回顾队列来确定与霉酚酸酯不良反应相关的变异 使用高通量定制单核苷酸多态(SNP)芯片进行分析(测试队列) 然后是使用低通量基因分型方法的预期队列(验证队列)。考虑到 甲孕酮完全由UGT酶进行葡萄糖醛酸化，低浓度的甲孕酮与 较高的急性排斥发生率和高浓度与毒性相关，识别 具有导致药物暴露改变的变异的个人可能导致个性化的剂量和识别 病人处于危险之中。AIMS III和IV将研究以前确定的(从文献中)和新的 细胞色素P450(CYP)3A4/5酶和药物的遗传变异(从SNP芯片鉴定) 转运体与他克莫司、环孢素和西罗莫司的药代动力学及不良反应。当前数据 关于细胞色素P450和转运蛋白变体与药代动力学的关系是相互矛盾的，也是 临床预测能力较弱。因此，可能存在其他尚未确定的变种。我们将确定 候选变异与药代动力学和不良反应相关，通过使用 SNPChip随后在使用低通量基因分型的前瞻性验证队列中进行验证。vt.给出 CyP3A5和转运蛋白变异频率存在显著的种族差异， 将评估非裔美国人和高加索人的药代动力学。目标五号将决定 AIMS I-IV中确定的基因变异与临床结果(急性排斥和慢性排斥)之间的关系 移植物功能障碍)。我们希望这个项目的结果将帮助照顾者选择和剂量 免疫抑制治疗，以减少排斥反应，促进更好的移植物存活率，以减少药物 毒性，并提高移植受者的总体存活率。

The overall objective of this project is to test the hypothesis that relationships between specific genetic variants of drug metabolizing enzymes, drug transporters, drug targets and biological pathways are associated with pharmacokinetics and adverse effects of immune suppressants, and clinical outcomes in 5000 ethnically diverse kidney transplant recipients. Aims I and II will determine the associations between donor and recipient genetic variants of the glucuronosyltransferase (UGT) enzymes and drug transporters, with mycophenolic acid (MPA) pharmacokinetics and mycophenolote mofetil (MMF) related toxicity. For Aim I, known UGT enzyme and transporter variant genotypes will be assessed in recipient and donor DMA using traditional low throughput genotyping methods. MPA pharmacokinetics will be measured in the recipient. In Aim II, we will identify the variants associated with MMF adverse effects through a retrospective cohort analysis (Test Cohort) using a high throughput customized single nucleotide polymorphism (SNP) Chip followed by a prospective cohort (Validation Cohort) using low throughput genotyping methods. Given that MPA is exclusively glucuronidated by UGT enzymes, that low MPA concentrations are associated with a higher incidence of acute rejection, and high concentrations are associated with toxicity, identifying individuals with variants leading to altered drug exposure could lead to individualized dosing and identify patients at risk. Aims III and IV will study the association of previously identified (from the literature) and new genetic variants (identified from the SNPChip) of cytochrome P450 (CYP) 3A4/5 enzymes and drug transporters with tacrolimus, cyclosporine and sirolimus pharmacokinetics and adverse effects. Current data regarding the relationship of CYP and transporter variants with pharmacokinetics are conflicting and are too weak for clinical prediction. Hence, other yet unidentified variants may be present. We will identify the candidate variants associated with pharmacokinetics and adverse effects through a Test Cohort using the SNPChip followed by validation in a prospective Validation Cohort using low throughput genotyping. Given that there are significant ethnic differences in CYP 3A5 and transporter variant frequencies, the pharmacokinetics will be evaluated in African Americans and Caucasians. Aim V will determine the association between genetic variants identified in Aims I-IV and clinical outcomes (acute rejection, and chronic graft dysfunction). We expect the results of this project will help caregivers in the selection and dosing of immunosuppressant therapies to minimize rejection episodes and foster better graft survival, to lower drug toxicity, and to improve overall survival of transplant recipients.