Genomics of Kidney Transplantation

描述（由申请人提供）：我们的联盟由7个中心组成，每年共进行约1000例肾脏移植；该联盟现在被资助研究肾移植受者的慢性移植物功能障碍。我们的资助将用于建立一个多中心数据库，收集供体和受体的人口统计数据、肾活检信息和受体结果。在当前的应用中，我们建议（使用已建立的基础设施）研究遗传变异是否在一定程度上导致了接受类似免疫抑制方案治疗的移植受者的不同结果。我们的长期目标是确定是否有可能根据遗传学进行个体化免疫抑制治疗，以尽量减少排斥反应，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的项目（The Genetic Epidemiology of study of Kidney Alloqraft Function）有两个具体目的：1)研究移植受体基因（细胞因子、趋化因子、纤维化因子、血栓形成因子、生长因子、血管细胞粘附分子和高血压）等位基因变异与慢性同种异体移植功能障碍和肾小球滤过率（eGFR）的关系；II)研究慢性同种异体移植物功能障碍的活体供体基因等位变异与eGFR的关系。我们还将研究活体供体和受体基因型对慢性同种异体移植物功能障碍和eGFR的相互作用。Jacobson项目（肾移植免疫抑制剂的药物遗传学）有5个具体目标：目标1和目标2将确定供体和受体之间葡萄糖醛基转移酶（UGT）酶和药物转运体的遗传变异以及霉酚酸（MPA）药代动力学和霉酚酸（MMF）相关毒性的关系。目的III和IV将确定先前发现的和新的CYP 3A4/5酶遗传变异与药物转运体对他克莫司、环孢素和西罗莫司全身浓度和不良反应的关系。Aim将确定Aims I-IV中发现的遗传变异与其他变异（如药物靶点和临床结果）之间的关系。三个核心单位——一个行政核心、一个临床和生物统计核心以及一个基因分型核心——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.