Pharmacogenomics of Immune Suppressants in Kidney Transplantation

我们建议研究钙调神经磷酸酶抑制剂(CNI)和霉酚酸酯在肾移植中的药物基因组学。尽管这些药物提供了巨大的治疗进展，但它们的使用仍然受到毒性和治疗失败的限制。不幸的是，我们无法辨别哪些患者会出现毒性或治疗失败。对于这些患者来说，后果可能是严重的，包括恢复到 透析、再次移植和死亡。对血液水平的监测提高了我们在免疫抑制开始后改善和量身定制治疗的能力；然而，初始剂量在很大程度上是经验性的，并使用粗暴的“一刀切”方法。这导致相当数量的患者处于亚治疗和超治疗水平。也有相当数量的患者尽管达到了治疗水平 会导致治疗失败并产生毒性。我们将通过这一应用解决主要的治疗限制--毒性和失败。基因变异可能是预测谁会出现毒性或治疗失败的重要因素。我们将在3000名肾移植受者中进行全基因组关联研究，以确定与他克莫司血药浓度和钙调神经磷酸酶抑制物相关的单核苷酸多态。 (CNI)相关的肾毒性、免疫抑制相关的移植后新发糖尿病(NODAT)以及与霉酚酸酯相关的白细胞减少和贫血。然后，这一发现将在另外3000名肾移植接受者中得到验证。我们还将研究600名受助者中的SNPs之间的关系 药理靶点，CN和肌苷单磷酸脱氢酶(IMPDH)，这些靶点的mRNA表达，它们在PBMCs中的蛋白活性以及排斥反应和毒性。我们的目标是利用临床因素和SNP为CNI开发临床剂量模型，以便我们能够个体化给药，并识别与CNI或霉酚酸酯毒性相关的遗传因素，以便可以为避免或最大限度地减少风险因素而定制治疗方案(S)。长期目标是为每个患者提供适合他们的剂量和毒性风险最低、成功率最高的免疫抑制方案。然后，本项目中确定的SNPs将与项目1中确定的对急性排斥、慢性移植物功能障碍和移植物衰竭具有重要作用的重要SNPs结合起来。

We propose to investigate the pharmacogenomics ofthe calcineurin inhibitors (CNI) and mycophenolate in kidney transplantation. Despite the tremendous therapeutic advances that these drugs have provided, their use is still limited by toxicities and therapy failures. Unfortunately, we are unable to discern which patients will develop toxicity or fail therapy. For these patients the consequences can be severe including return to dialysis, retransplantation and death. Monitoring of blood levels has improved our ability to improve and tailor therapy once immune suppression is initiated; however, initial doses are largely empiric and use the crude "one size fits all" approach. This results in subtherapeutic and supratherapeutic levels in a substantial number of patients. There are also a substantial number oif patients who despite achieving therapeutic levels will fail therapy and develop toxicity. We will address major therapy limitations - toxicity and failure - through this application. Genetic variation may be an important factor in predicting who will develop toxicity or fail therapy. We will conduct a genome wide association study in 3000 kidney transplant recipients to define single nucleotide polymorphisms (SNPs) associated with tacrolimus blood levels, and calcineurin inhibitor (CNI) related nephrotoxicity, immune suppressant related new onset diabetes after transplant (NODAT), and mycophenolate related leukopenia and anemia. The findings will then be validated in 3000 additional kidney transplant recipients. We will also study, in a subset of 600 recipients, the relationships between SNPs of the pharmacologic targets, CN and inosine monophosphatase dehydrogenase (IMPDH), mRNA expression of these targets, their protein activity in PBMCs and rejection and toxicities. Our goal is to develop clinical dosing models for the CNIs using clinical factors and SNPs such that we can individualize dosing and to identify genetic factors associated with CNI or mycophenolate toxicities such that regimens may be individually tailored to avoid or minimize the risk agent(s). The long term goal is to provide every patient the dose appropriate for them and the immunosuppressive regimen with the lowest toxicity risk and highest success. SNPs identified in this project will then be combined with important SNPs identified as important towards acute rejection, chronic graft dysfunction and graft failure in project 1.