Pharmacogenomics of Immune Suppressants in Kidney Transplantation

我们拟研究钙调磷酸酶抑制剂（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，后果可能很严重，包括再次透析、再次移植和死亡。一旦免疫抑制开始，监测血液水平提高了我们改善和定制治疗的能力;然而，初始剂量主要是经验性的，并使用粗糙的“一刀切”方法。这导致亚治疗和超治疗水平， 患者人数。还有相当数量的oif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以下方法解决主要的治疗局限性-毒性和失败- 这个应用程序。遗传变异可能是预测谁会产生毒性或失败的重要因素 疗法我们将在3000名肾移植受者中进行全基因组关联研究， 与他克莫司血药浓度和钙调磷酸酶抑制剂相关的单核苷酸多态性 (CNI)相关肾毒性、免疫抑制剂相关移植后新发糖尿病（NODAT），以及 霉酚酸盐相关的白细胞减少症和贫血。这些发现将在另外3000个肾脏中得到验证 移植接受者我们还将在一个600名接受者的子集中研究， 药理学靶点，CN和肌苷单磷酸酶脱氢酶（IMPDH）， 这些靶点、它们在PBMC中的蛋白质活性以及排斥和毒性。我们的目标是发展临床 使用临床因素和SNP的CNI给药模型，以便我们可以个性化给药， 确定与CNI或霉酚酸酯毒性相关的遗传因素， 单独定制以避免或最小化风险因素。长期目标是为每一位患者提供 剂量适合他们和免疫抑制方案具有最低的毒性风险和最高的 成功本项目中确定的SNP将与重要的SNP结合， 急性排斥反应、慢性移植物功能障碍和移植物衰竭。

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.