Genomics of Kidney Transplantation

描述(由申请人提供)：我们的联盟由7个中心组成，每年总共进行约1000例肾移植；该联盟现在被资助用于研究肾移植受者的慢性移植功能障碍。我们资助的赠款为建立多中心数据库提供支持，并收集关于捐赠者和接受者的人口统计数据、肾脏活检信息和接受者结局的数据。在目前的应用中，我们建议(利用已建立的基础设施)研究基因变异是否在一定程度上导致了接受类似免疫抑制治疗的移植受者的不同结果。我们的长期目标是确定基于遗传学的个体化免疫抑制治疗是否可能，以最大限度地减少排斥反应，降低药物毒性，并提高患者和移植物的长期存活率。我们的应用程序由2个项目和3个核心组成。ISRANI(肾脏移植功能恶化的遗传流行病学)项目有2个具体目标：1)研究移植受体基因的等位变异(细胞因子、趋化因子、纤维化因子、血栓形成因子、生长因子、血管细胞黏附分子和高血压)与慢性移植肾功能障碍和估计肾小球滤过率(EGFR)的关系；2)研究活体供者基因等位变异与慢性移植肾功能障碍和EGFR的关系。我们还将研究活体供者和受者基因对慢性同种异体移植功能障碍和EGFR的影响。Jacobson的项目(肾脏移植中免疫抑制药物的药物遗传学)有5个具体目标：AIMS I和II将确定供体和受体之间葡萄糖醛酸基转移酶(UGT)酶的遗传变异和药物转运体之间的关系，以及霉酚酸(MPA)的药代动力学和霉酚酸酯(MMF)相关的毒性。AIMS III和IV将建立以前发现的和新的CyP3A4/5酶和药物转运体之间的联系，这些酶和药物转运体对他克莫司、环孢素和西罗莫司的全身浓度和不良反应有关联。AIM将确定AIMS I-IV中确定的遗传变异与其他变异之间的联系，如药物靶点和临床结果。三个核心单位--一个行政核心、一个临床和生物统计核心和一个基因分型核心--将促进拟议的研究。

DESCRIPTION (provided by applicant): Our consortium consists of 7 centers which do a total of approximately 1000 kidney transplants/year; the consortium is now funded to study chronic graft dysfunction in kidney transplant recipients. Our funded grant provides support for establishing a multicenter database, and collecting data on donor and recipient demographics, kidney biopsy information, and recipient outcome. In the current application, we propose (using the infrastructure established) to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with similar immunosuppressive protocols. Our long-term goals are to determine whether it will be possible to individualize immunosuppressive therapy based on genetics in order to minimize rejection episodes, to lower drug toxicity, and improve long-term patient and graft survival. Our application consists of 2 Projects and 3 cores. Project by Israni (The Genetic Epidemiology of Deterioration of Kidney Alloqraft Function) has 2 specific aims: I) to study the relationships between allelic variants of transplant recipient genes (for cytokines, chemokines, fibrotic factors, thrombotic factors, growth factors, vascular cell adhesion molecules and hypertension) with chronic allograft dysfunction and estimated glomerular filtration rate (eGFR); II) to study the relationships between allelic variants of living donor genes with chronic allograft dysfunction and eGFR. We will also study the interaction of living donor and recipient genotypes on chronic allograft dysfunction and eGFR. Project by Jacobson (Pharmacogenetics of Immune Suppressants in Kidney Transplantation) has 5 specific Aims: Aims I and II will determine the relationships between donor and recipient genetic variants of the glucuronosyltransferase (UGT) enzymes and drug transporters, and mycophenolic acid (MPA) pharmacokinetics and mycophenolote mofetil (MMF) related toxicity. Aims III and IV will establish the association between previously identified and new genetic variants of CYP 3A4/5 enzymes and drug transporters on tacrolimus, cyclosporine and sirolimus systemic - concentrations and adverse effects. Aim \/ will determine the association between genetic variants identified in Aims I-IV and other variants such as drug targets and clinical outcomes. Three core units - an Administrative Core, a Clinical and Biostatistical Core and a Genotyping Core - will facilitate the proposed research.