Genomics of Kidney Transplantation Admin

肾移植管理的基因组学

• 批准号: 8709803
• 负责人: ARTHUR J MATAS
• 金额: $ 170.51万
• 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/8709803
• 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.

本拨款申请是对RFA-AI-10-019的回应。我们有a)一个已建立的财团，由