Genomics of Kidney Transplantation Admin

此拨款申请是对RFA-AI-10-019的回应。我们有一个）成立的财团， 5个临床中心，每年共进行>800例肾移植; B）开发了一种质量控制的 高质量数据的多中心数据库，并在撰写本文时c）获得了DNA样本和临床数据 2865名接受者和1010名捐赠者。我们建议（利用我们已发展的基础设施）研究是否 遗传变异在一定程度上导致了移植受者的不同结果， 现代免疫抑制方案。我们的中心假设是，遗传变异与 a）肾移植结果，和B）免疫抑制药物处置和毒性。我们的长期 目的是确定是否有可能根据以下因素进行个体化免疫抑制治疗： 遗传学与此同时，我们的研究可能会引出关于免疫重要途径的新信息。 反应或免疫抑制药物功效、处置和毒性。我们的应用程序包括2 项目和3个核心。我们将使用测试和验证进行全基因组关联研究（GWAS）。 队列设计将使用GWAS在测试群组（3000名接受者和1000名受试者）中鉴定显著的SNP。 1 000名捐助者）。然后，将在来自3000名接受者和1300名接受者的样本分析中验证重要的SNP。 捐助者在整个更新期间登记。项目1将研究与移植结果相关的SNP 目标1：识别受体单核苷酸多态性（SNP）， 与肾移植结局（急性排斥反应、慢性移植物功能障碍和移植物衰竭）相关。目的 2：确定与肾移植结局相关的活体供体SNP。项目2.有4 具体目标。目的1：鉴定与他克莫司血药浓度相关的SNPs;目的2：鉴定SNPs 与早期他克莫司相关肾毒性和免疫抑制剂相关新发糖尿病相关; 目的3：鉴定与麦考酚酯相关毒性相关的SNPs。我们的目标4：建立 候选受体SNP、酶活性和mRNA表达之间的关系 麦考酚酯和钙调磷酸酶抑制剂的药理学靶点。这些项目相互关联， 三个核心支持这两个项目。这些项目使用相同的DNA和基因分型数据（由 遗传学核心）和临床信息（由临床研究中心收集并输入多中心数据库）。 核心）。此外，生物统计支持（临床核心）和行政监督和支持（行政 核心）将促进两者的数据收集、数据输入和数据分析。行政核心还将 促进站点、核心和项目之间的交互。

This grant application is a response to RFA-AI-10-019. We have a) an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year; b) developed a quality-controlled multicenter database with high quality data, and as ofthis writing c) obtained DNA samples and clinical data on 2865 recipients and 1010 donors. We propose (using our developed infrastructure) to study whether genetic variants are, in part, responsible forthe differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that genetic variation is associated with: a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it will be possible to individualize immunosuppressive therapy based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity. Our application consists of 2 Proiects and 3 Cores. We will do a genome wide association study (GWAS) using a test and validation cohort design. Significant SNPs will be identified using the GWAS in a test cohort (of 3000 recipients and 1000 donors). Important SNPs will then be validated in analyses of samples from 3000 recipients and 1300 donors enrolled throughout this renewal. Project 1 will study SNPs that are associated with graft outcome and has 2 Specific Aims ¿ Aim 1: To identify recipient single nucleotide polymorphisms (SNPs) that are associated with kidney allograft outcomes (acute rejection, chronic graft dysfunction and graft failure). Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. Proiect 2. has 4 Specific Aims. Aim 1: To identify SNPs associated with tacrolimus blood levels; Aim 2: to identify SNPs associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes; Aim 3; to identify SNPs associated with mycophenolate-related toxicity. Our Aim 4: is to establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression ofthe pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects are highly interrelated and the 3 Cores support both Projects. The Projects use the same DNA and genotyping data (provided by the Genetics Core), and clinical information (collected and entered into the multicenter database by the Clinical Core). Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.