Pharmacogenetics of Immune Suppressants in Kidney Transplantation

本项目的总体目标是检验特定遗传因素之间的关系 药物代谢酶、药物转运蛋白、药物靶标和生物途径的变体， 与免疫抑制剂的药代动力学和不良反应相关， 5000名不同种族的肾移植受者。目标一和目标二将决定 葡萄糖醛酸基转移酶（UGT）酶和药物转运蛋白的供体和受体遗传变体， 与霉酚酸（MPA）药代动力学和霉酚酸酯（MMF）相关的毒性。为宗旨 I，已知的UGT酶和转运蛋白变体基因型将在受体和供体DMA中使用 传统的低通量基因分型方法。将在接受者中测量MPA药代动力学。在 目的II，我们将通过回顾性队列研究确定与MMF不良反应相关的变异 使用高通量定制的单核苷酸多态性（SNP）芯片进行分析（测试队列） 随后是使用低通量基因分型方法的前瞻性队列（验证队列）。鉴于 MPA仅被UGT酶葡萄糖醛酸化，低MPA浓度与 急性排斥反应的发生率较高，高浓度与毒性相关， 具有导致药物暴露改变的变异的个体可能导致个体化给药， 患者有风险。目的III和IV将研究先前确定的（来自文献）和新的 细胞色素P450（CYP）3A 4/5酶和药物的遗传变异体（从SNPChip中鉴定） 转运体与他克莫司、环孢素和西罗莫司的药代动力学和不良反应。当前数据 关于β-内酰胺酶和转运蛋白变异体与药代动力学的关系， 临床预测能力弱。因此，可能存在其他尚未识别的变体。我们将确定 通过试验队列，使用 SNPChip随后使用低通量基因分型在前瞻性验证队列中进行验证。给定 有显着的种族差异，在α 3A 5和转运蛋白变异频率， 将在非裔美国人和高加索人中评价药代动力学。目标五将决定 目的I-IV中鉴定的遗传变异与临床结果（急性排斥和慢性排斥）之间的相关性 移植物功能障碍）。我们希望这个项目的结果将有助于护理人员在选择和剂量的 免疫抑制剂治疗，以尽量减少排斥反应的发生，促进更好的移植物存活，以减少药物 毒性，并提高移植受体的总体存活率。

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.