Genomics of Kidney Transplantation Admin

肾移植管理的基因组学

• 批准号: 8307773
• 负责人: ARTHUR J MATAS
• 金额: $ 166.26万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307773
• 关键词: Acute; Applications Grants; Biopsy; Blood; Calcineurin; Calcineurin inhibitor; Chronic; Clinical; Clinical Data; Creatinine; DNA; Data; Data Analyses; Data Collection; Data Quality; Data Set; Databases; Diabetes Mellitus; Drug toxicity; Enrollment; Failure; Functional disorder; Genetic; Genetic Variation; Genomics; Genotype; Goals; Graft Rejection; Graft Survival; Immune; Immune response; Immunosuppressive Agents; Inosine; Instruction; Kidney Transplantation; Lead; Letters; Link; Living Donors; Meta-Analysis; Mycophenolate; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Protocols documentation; Quality Control; Research; Research Infrastructure; Sampling; Single Nucleotide Polymorphism; Site; Tacrolimus; Testing; Therapeutic immunosuppression; Time; Toxic effect; Transplant Recipients; Transplantation; Validation; Writing; base; cohort; design; drug efficacy; enzyme activity; genetic variant; genome wide association study; genome-wide; graft failure; improved; kidney allograft; mRNA Expression; nephrotoxicity; novel; programs; response

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.

该拨款申请是对 RFA-AI-10-019 的回应。我们有一个已建立的联盟，包括 5个临床中心，每年总共进行>800例肾移植； b) 开发了一个质量控制的 具有高质量数据的多中心数据库，截至撰写本文时 c) 获得的 DNA 样本和临床数据 2865 名受赠者和 1010 名捐赠者。我们建议（使用我们发达的基础设施）研究是否 遗传变异在一定程度上是造成移植受者治疗结果不同的原因 现代免疫抑制方案。我们的中心假设是遗传变异与 包括：a) 肾移植结果，b) 免疫抑制药物的处置和毒性。我们的长期 目标是确定是否有可能基于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发有关免疫重要途径的新信息。 反应或免疫抑制药物的功效、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 在测试队列（3000 名接受者和 1000 名捐助者）。然后，重要的 SNP 将在来自 3000 名接受者和 1300 名接受者的样本分析中得到验证 捐助者在本次更新期间登记。项目 1 将研究与移植结果相关的 SNP 并有 2 个具体目标 ¿ 目标 1：识别受者单核苷酸多态性 (SNP) 与肾同种异体移植结果（急性排斥、慢性移植物功能障碍和移植物衰竭）相关。目的 2：确定与肾同种异体移植结果相关的活体供体 SNP。项目 2. 有 4 具体目标。目标 1：确定与他克莫司血液浓度相关的 SNP；目标 2：识别 SNP 与早期他克莫司相关的肾毒性和免疫抑制相关的新发糖尿病有关； 目标3；识别与霉酚酸酯相关毒性相关的 SNP。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 霉酚酸酯和钙调神经磷酸酶抑制剂的药理靶点。这些项目高度相关且 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多中心数据库） 核）。此外，生物统计支持（临床核心）以及行政监督和支持（行政管理） Core）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。