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

• 批准号: 10171772
• 负责人: Rasheed Adebayo Gbadegesin
• 金额: $ 78.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10171772
• 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; 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; Lead; Life; Link; MHC Class II Genes; Mediating; Membranous Glomerulonephritis; Midwestern United States; Modeling; Molecular; Nephrology; Nephrotic Syndrome; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Recurrence; Relapse; Renal glomerular disease; Resistance; Resolution; Risk; Risk Factors; Role; Secondary to; Steroid Resistance; Steroids; Stratification; Structure; T-Lymphocyte; Testing; Therapeutic Trials; Thromboembolism; Transplantation; Untranslated RNA; Variant; adaptive immunity; care burden; cohort; design; disorder risk; experimental study; genetic variant; 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

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）是一种知识渊博的免疫介导的肾脏疾病。在儿童中，所有情况中有80％ 具有类固醇的反应性，被称为类固醇敏感的NS（SSN），而其他20％是类固醇 抗性（SRN）。 SRNS是需要透析和肾脏的终末期肾脏疾病的主要原因 移植；不幸的是，60％的SRN患者将在移植后发展疾病复发 最终导致肾脏同种异体衰竭。我们和其他人证明了人类白细胞中的变体 抗原（HLA）基因与NS相关，表示自适应免疫缺陷，涉及失调 T和B淋巴细胞均可能是NS发病机理的中心。而HLA和NS之间的关联 很强，先前的研究是使用基因组范围芯片在小型单种族人群中进行的 HLA基因的覆盖范围有限，并且变体发现了NS风险的一小部分。所以， 与NS相关的精确HLA等位基因/单倍型仍然未知。为了增强我们对NS的理解， 我们和其他人已经招募了3,700多名主要，继发性和移植后NS的多民族患者 来自主要的多中心肾脏疾病研究。我们建议执行下一代艺术状态 主要HLA I和II类基因的编码和非编码区的测序（NGS）以确定 这些基因中变体之间的关系以及NS的风险，对治疗的反应和疾病复发 肾脏移植后。我们的总体假设是某些HLA等位基因/单倍型 与NS相关的可以预测原发性NS中皮质类固醇反应的模式和疾病的风险 肾脏移植后的复发。我们将检验我们的假设并评估潜在的分子 通过以下目的的机制：1）使用高分辨率HLA识别NS HLA风险等位基因/单倍型 多种族患者队列中的NGS，并确定基因型与治疗之间的关系 反应，2）研究主要NS HLA风险等位基因/单倍型与次要原因之间的关联 免疫介导的NS（IgA和膜肾病），3）确定常见的结构和功能 NS HLA内的图案风险等位基因/单倍型和非风险等位基因通过silico建模和比较基因，并且 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，4）确定能力 已知和新型的NS HLA风险单倍型预测肾脏移植后疾病复发。 意义：本应用中提出的研究将使用主要的HLA基因的最先进的NG进行 确定与NS，治疗反应和疾病相关的精确HLA等位基因/单倍型 肾脏移植后的复发。了解HLA变体和自适应的内在作用 NS的免疫功能障碍将导致鉴定在疾病中很重要的新途径 发病机理和治疗不仅适用于NS，还适用于其他常见的肾小球疾病。