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。我们的资助金为建立多中心数据库提供支持，并收集供体和受体人口统计学数据，肾活检信息和受体结局。在本申请中，我们提出（使用已建立的基础设施）研究遗传变异是否部分地对用类似免疫抑制方案治疗的移植受者的不同结果负责。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，以减少排斥反应，降低药物毒性，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。项目Israni《同种异体肾功能恶化的遗传流行病学》有两个具体目标：1）研究移植受体基因的等位变异之间的关系（对于细胞因子、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）伴慢性同种异体移植物功能障碍和估计肾小球滤过率（eGFR）; II）研究活体供者基因等位变异与慢性移植物功能障碍和eGFR的关系。我们还将研究活体供者和受体基因型对慢性移植物功能障碍和eGFR的相互作用。Jacobson的项目（肾移植免疫抑制剂的药物遗传学）有5个特定目的：目的I和II将确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异体之间的关系，以及麦考酚酸（MPA）的药代动力学和麦考酚酸酯（MMF）相关毒性。目的III和IV将建立先前鉴定的和新的基因变体的α 3 A4/5酶和药物转运蛋白对他克莫司、环孢菌素和西罗莫司全身浓度和不良反应之间的关联。目的将确定目的I-IV中鉴定的遗传变异与其他变异（如药物靶点和临床结果）之间的关联。三个核心单位-行政核心，临床和生物统计核心和基因分型核心-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.