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: 10413024
• 负责人: Rasheed Adebayo Gbadegesin
• 金额: $ 77.51万
• 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/10413024
• 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; 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.

项目概要 肾病综合征（NS）是一种人们知之甚少的免疫介导的肾脏疾病。 80% 的病例发生在儿童身上 对类固醇有反应，被称为类固醇敏感 NS (SSNS)，而另外 20% 是类固醇 耐药（SRNS）。 SRNS 是需要透析和肾脏治疗的终末期肾病的主要原因 移植；不幸的是，60% 的 SRNS 患者在移植后会出现疾病复发 最终导致同种异体肾移植失败。我们和其他人已经证明人类白细胞的变异 抗原 (HLA) 基因与 NS 相关，表明适应性免疫缺陷，包括失调 T 和 B 淋巴细胞的共同作用，可能是 NS 发病机制的核心。虽然 HLA 和 NS 之间的关联 很强大，之前的研究是使用全基因组关联芯片在小型单种族队列中进行的 HLA 基因的覆盖范围有限，并且发现的变异只占 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。为了加深我们对 NS 的理解， 我们和其他人已经招募了 3,700 多名患有原发性、继发性和移植后 NS 的多种族患者 来自主要的多中心肾脏疾病研究。我们建议下一代执行最先进的技术 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。我们的首要假设是某些 HLA 等位基因/单倍型 与 NS 相关可以预测原发性 NS 的皮质类固醇反应模式和疾病风险 肾移植后复发。我们将检验我们的假设并评估潜在的分子 通过以下目标实现机制： 1) 使用高分辨率 HLA 识别 NS HLA 风险等位基因/单倍型 对多种族患者队列进行 NGS 并确定基因型与治疗之间的关系 响应，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 和膜性肾病）的研究，3) 确定常见的结构和功能 通过计算机模拟分析 NS HLA 风险等位基因/单倍型和非风险等位基因中的基序，并比较基因和 NS 患者 B 淋巴细胞和肾脏中这些等位基因的蛋白表达，以及 4) 确定能力 已知和新的 NS HLA 风险单倍型用于预测肾移植后疾病复发。 意义：本申请提出的研究将利用主要 HLA 基因的尖端 NGS 识别与 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。了解 HLA 变异和适应性的内在作用 NS 中的免疫功能障碍将导致识别疾病中重要的新途径 发病机制和治疗不仅适用于 NS，还适用于其他常见肾小球疾病。