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Defining the Landscape of HLA Risk Alleles in Primary Nephrotic Syndrome and Post Kidney Transplant Recurrence

定义原发性肾病综合征和肾移植后复发中 HLA 风险等位基因的分布

基本信息

批准号：
10623182
负责人：
Rasheed Adebayo Gbadegesin
金额：
$ 75.01万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623182
关键词：
Adrenal Cortex Hormones Alleles Allografting B-Lymphocytes Blood specimen Cardiovascular system Child Childhood Clinical Clinical Research Clinical Trials Code Cohort Studies Data Defect Development Dialysis procedure Disease Disease remission End stage renal failure Enrollment Ethnic Origin Failure Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genotype HLA Antigens Haplotypes Healthcare Histocompatibility Antigens Class I IGA Glomerulonephritis Immune Infection Kidney Kidney Diseases Kidney Transplantation Life Link MHC Class II Genes Mediating Membranous Glomerulonephritis Midwestern United States Modeling Molecular Nephrology Nephrotic Syndrome Pathogenesis Pathway interactions Patients Pattern Peptides Recurrence Recurrent disease Relapse Renal glomerular disease Resolution Risk Risk Factors Role Secondary to Steroid Resistance Steroids Stratification Testing Therapeutic Trials Thromboembolism Transplantation Untranslated RNA Variant adaptive immunity care burden cohort design disorder risk experimental study genome sequencing genome wide association study in silico individualized medicine insight kidney allograft kidney biopsy multi-ethnic new therapeutic target next generation sequencing novel peripheral blood post-transplant precision medicine primary nephrotic syndrome protein expression response risk variant treatment response whole genome

项目摘要

PROJECT SUMMARY Nephrotic syndrome (NS) is a poorly understood immune-mediated kidney disease. In children, 80% of all cases are steroid responsive and are referred to as steroid sensitive NS (SSNS), while the other 20% are steroid resistant (SRNS). SRNS is a major cause of end-stage kidney disease requiring dialysis and kidney transplantation; unfortunately, 60% of patients with SRNS will develop disease recurrence following transplant and ultimately kidney allograft failure. We and others have demonstrated that variants in Human Leukocyte Antigen (HLA) genes are associated with NS, signifying that defects in adaptive immunity, involving dysregulation of both T and B lymphocytes, may be central to NS pathogenesis. While the association between HLA and NS is strong, previous studies were carried out in small mono-ethnic cohorts using genome wide association chips with limited coverage of the HLA genes, and variants uncovered account for a small fraction of NS risk. Therefore, the precise HLA alleles/haplotypes associated with NS remain unknown. To enhance our understanding of NS, we and others have enrolled over 3,700 multi-ethnic patients with primary, secondary, and post-transplant NS from major multicenter kidney disease studies. We propose to perform state of the art next generation sequencing (NGS) of the coding and non-coding regions of major HLA class I and II genes to determine the relationship between variants in these genes and risk of NS, response to therapy, and disease recurrence following kidney transplantation. Our overarching hypothesis is that certain HLA alleles/haplotypes associated with NS can predict pattern of corticosteroid response in primary NS and the risk of disease recurrence following kidney transplantation. We will test our hypothesis and evaluate potential molecular mechanisms through the following aims: 1) Identify NS HLA risk alleles/haplotypes using high resolution HLA NGS in a cohort of multi-ethnic patients and determine the relationship between genotypes and therapy response, 2) Investigate the association between primary NS HLA risk alleles/haplotypes and secondary causes of immune-mediated NS (IgA and membranous nephropathy), 3) Determine common structural and functional motifs within NS HLA risk alleles/haplotypes and non-risk alleles by in-silico modeling and compare gene and protein expression of these alleles in B lymphocytes and kidneys of patients with NS, and 4) Determine the ability of known and novel NS HLA risk haplotypes to predict disease recurrence following kidney transplantation. Significance: The studies proposed in this application will use cutting-edge NGS of major HLA genes to identify the precise HLA alleles/haplotypes that are associated with NS, therapy response, and disease recurrence following kidney transplantation. Understanding the intrinsic role of HLA variants and adaptive immunity dysfunction in NS will lead to identification of novel pathways that are important in disease pathogenesis and therapy not just for NS, but also for other common glomerular diseases.

项目摘要肾病综合征（NS）是一种免疫介导的肾脏疾病。在儿童中，80%的病例是类固醇反应性的，被称为类固醇敏感性NS（SSNS），而其他20%是类固醇抗性（SRNS）。SRNS是需要透析和肾功能衰竭的终末期肾病的主要原因。不幸的是，60%的SRNS患者在移植后会出现疾病复发最终导致肾移植失败我们和其他人已经证明，人类白细胞中的变异抗原（HLA）基因与NS相关，表明适应性免疫缺陷，涉及失调 T淋巴细胞和B淋巴细胞的免疫调节可能是NS发病机制的核心。HLA与NS的相关性是强大的，以前的研究是在小的单一种族队列中使用全基因组关联芯片进行的。 HLA基因的覆盖率有限，未发现的变异占NS风险的一小部分。因此，我们认为，与NS相关的精确的HLA等位基因/单倍型仍然未知。为了加深我们对NS的理解，我们和其他研究人员已经招募了3,700多名患有原发性、继发性和移植后NS的多种族患者主要的多中心肾脏疾病研究。我们打算为下一代的艺术家通过对主要HLA I类和II类基因的编码区和非编码区进行测序（NGS），以确定这些基因变异与NS风险、治疗反应和疾病复发之间的关系肾移植后。我们的总体假设是，某些HLA等位基因/单倍型可预测原发性NS皮质类固醇反应模式和疾病风险肾移植后复发。我们将测试我们的假设，并评估潜在的分子 1）使用高分辨率HLA鉴定NS HLA风险等位基因/单倍型 NGS在多种族患者队列中的应用，并确定基因型与治疗之间的关系 2）调查原发性NS HLA风险等位基因/单倍型与继发性原因之间的关联免疫介导的NS（伊加和膜性肾病），3）确定共同的结构和功能 NS HLA风险等位基因/单倍型和非风险等位基因内的基序，这些等位基因在NS患者的B淋巴细胞和肾脏中的蛋白质表达，以及4）确定这些等位基因在NS患者的肾脏中的表达能力。已知和新的NS HLA风险单倍型预测肾移植后疾病复发。意义：本申请中提出的研究将使用主要HLA基因的尖端NGS，确定与NS、治疗反应和疾病相关的精确HLA等位基因/单倍型肾移植后复发。理解HLA变体的内在作用和适应性 NS中免疫功能障碍将导致识别疾病中重要的新途径不仅对NS的发病机制和治疗，而且对其他常见的肾小球疾病也有重要意义。