Genomics of Kidney Transplantation Admin

该拨款申请是对RFA-AI-10-019的响应。我们有a)一个由以下成员组成的成熟财团 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 具有高质量数据的多中心数据库，并且在撰写本文时c)获得了DNA样本和临床数据 2865名受赠者和1010名捐赠者。我们建议(利用我们已开发的基础设施)研究 基因变异是移植受者接受不同治疗结果的部分原因。 现代免疫抑制方案。我们的中心假设是遗传变异与 与：a)肾移植结果，以及b)免疫抑制药物处置和毒性。我们的长期合作 目标是确定是否有可能根据以下情况个体化免疫抑制治疗 遗传学。与此同时，我们的研究可能会在免疫中重要的途径上获得新的信息 或在免疫抑制药物的疗效、处置和毒性方面。我们的应用程序由2个 项目和3个核心。我们将使用测试和验证来进行全基因组关联研究(GWAS) 队列设计。重要的SNPs将在测试队列(3000名受试者和 1000名捐赠者)。然后，重要的SNPs将在3000名接受者和1300名接受者的样本分析中得到验证 捐赠者在整个续签过程中登记。项目1将研究与移植结果相关的SNPs 并有两个具体目标：目标1：识别符合以下条件的受体单核苷酸多态(SNP) 与肾移植结局(急性排斥、慢性移植功能障碍和移植失败)相关。目标 2：确定与肾移植预后相关的活体供者SNPs。项目2.有4个 明确的目标。目标1：识别与他克莫司血药浓度相关的SNPs；目标2：识别SNPs 与他克莫司相关的早期肾毒性和免疫抑制相关的新发糖尿病相关； 目的3：鉴定与霉酚酸酯相关毒性相关的SNPs。我们的目标4：建立 候选受体基因SNPs、酶活性与基因表达的关系 霉酚酸酯和钙调神经磷酸酶抑制剂的药理靶点。这些项目高度相关，而且 这3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(由临床中心收集并输入到多中心数据库中 核心)。此外，生物统计支助(临床核心)和行政监督和支助(行政 核心)将促进数据收集、数据录入和数据分析。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.