Genetics of IgA nephropathy by integrative network-based association studies

基于综合网络关联研究的 IgA 肾病遗传学

基本信息

批准号：
9258422
负责人：
KRZYSZTOF KIRYLUK
金额：
$ 42.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-17 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258422
关键词：
Address Affect Antibodies Antigen-Antibody Complex Architecture Autoimmune Process B-Lymphocytes Biological Markers Biopsy Cell Culture Techniques Cell Line Cells Characteristics Chromosome Mapping Complex Data Data Set Defect Deposition Development Disease Disease Pathway End stage renal failure Exhibits Family Far East Galactose Generations Genes Genetic Genetic Polymorphism Genotype Glomerulonephritis Heritability Human Herpesvirus 4 IGA Glomerulonephritis IgA1 Immune Immunoglobulin A In Vitro Individual Inflammation Injury Intervention Intestines Kidney Kidney Failure Maps Mediating Methods Modeling Molecular Molecular Profiling Natural Immunity Network-based Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Phase Phenotype Process Production RNA Interference Regulation Regulator Genes Resources Risk Serum Signal Transduction Specificity Suggestion Susceptibility Gene System Systems Biology Testing Therapeutic Intervention Tissues Validation adaptive immunity base biobank case control cohort disorder risk endophenotype experimental study follow-up genetic approach genome wide association study genome-wide glycosylation immortalized cell insight knock-down monocyte new therapeutic target novel overexpression population based public health relevance response risk variant transcriptome transcriptome sequencing transcriptomics ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the leading cause of renal failure in East Asia. The affected individuals develop characteristic IgA1-containing antibody complexes that deposit in the kidney, producing progressive renal injury. The disease is associated with a specific pathogenic defect in the O-glycosylation of IgA1 that promotes formation of immune complexes. Similar to other immune-mediated disorders, IgAN has a complex genetic architecture. In a recent GWAS involving 20,574 individuals, we identified 15 genome-wide significant susceptibility loci for IgAN. Our new loci implicated both adaptive and innate immunity in the disease pathogenesis and defined the "Network of Intestinal IgA Production" as the key pathogenic disease pathway. Based on our results, we developed an original multi-hit pathogenesis model that describes sequential steps and molecular candidates involved in the development of the disease. In this application, we propose to further refine this model by defining additional genetic hits involved in the defective regulation of mucosal IgA response. We specifically aim to discover additional IgAN susceptibility loci by a quantitative GWAS for serum levels for IgA and galactose-deficient IgA1 (Gd-IgA1). The GWAS discovery phase will include a well-powered multi-ethnic population-based cohort of 9,707 individuals. New genome-wide significant loci will be replicated independently and annotated using existing datasets and public resources. Next, through integrative network-based analyses, we will dissect precise pathogenic mechanisms behind each of the GWAS risk alleles. We will use a systems genetics approach that integrates RNA-seq and SNP microarray data to reconstruct gene regulatory networks in IgA1 secreting cells. Based on our network analyses, we will define master regulators and key drivers of the disease process. Our network predictions will be validated using experimental, computational, and genetic approaches. These studies are expected to refine the disease pathogenesis model and will be critical in defining potential targets for novel therapeutic interventions in IgAN.

描述（由申请人提供）：IgA 肾病 (IgAN) 是世界范围内最常见的原发性肾小球肾炎，也是东亚肾衰竭的主要原因，受影响的个体会出现特征性的含有 IgA1 的抗体复合物，沉积在肾脏中，产生进行性的进展。与其他免疫介导的疾病类似，该疾病与 IgA1 的 O-糖基化的特定致病性缺陷有关，该缺陷可促进免疫复合物的形成。 IgAN 具有复杂的遗传结构，在最近涉及 20,574 名个体的 GWAS 中，我们确定了 15 个全基因组显着的 IgAN 易感位点，我们的新位点与疾病发病机制有关，并定义了“肠道 IgA 产生网络”。根据我们的研究结果，我们开发了一种原始的多重发病机制模型，该模型描述了疾病发展中涉及的顺序步骤和分子候选物。在应用中，我们建议通过定义参与粘膜 IgA 反应缺陷调节的额外基因命中来进一步完善该模型，我们的具体目标是通过 IgA 和半乳糖缺陷 IgA1 (Gd-) 血清水平的定量 GWAS 发现额外的 IgAN 易感位点。 GWAS 发现阶段将包括一个由 9,707 个个体组成的强大的多种族群体队列。接下来，通过基于网络的综合分析，我们将使用整合 RNA 测序和 SNP 微阵列数据的系统遗传学方法来剖析每个 GWAS 风险等位基因背后的精确致病机制。根据我们的网络分析，重建 IgA1 分泌细胞中的基因调控网络，我们将通过实验、计算和验证来定义疾病过程的主调控因子和关键驱动因素。这些研究有望完善疾病发病机制模型，对于确定 IgAN 新型治疗干预的潜在靶点至关重要。