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

• 批准号: 8863093
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 43.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8863093
• 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; Gene Expression Profile; Generations; Genes; Genetic; Genetic Polymorphism; Genotype; Glomerulonephritis; Heritability; Human Herpesvirus 4; IgA1; Immune; Immunoglobulin A; In Vitro; Individual; Inflammation; Injury; Intervention; Intestines; Kidney; Kidney Diseases; Kidney Failure; Maps; Mediating; Methods; Modeling; Molecular; Molecular Profiling; Natural Immunity; Network-based; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Predisposition; Process; Production; RNA Interference; Regulation; Regulator Genes; Resources; Risk; Serum; Signal Transduction; Specificity; Susceptibility Gene; System; Systems Biology; Testing; Tissues; Validation; adaptive immunity; base; biobank; case control; cohort; disorder risk; endophenotype; follow-up; genetic approach; genome wide association study; genome-wide; glycosylation; immortalized cell; insight; knock-down; monocyte; novel; novel therapeutic intervention; overexpression; population based; public health relevance; research study; response; risk variant; transcriptome sequencing; transcriptomics; ubiquitin-protein ligase

 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）：伊加肾病（IgAN）是全球最常见的原发性肾小球肾炎，也是东亚肾衰竭的主要原因。受影响的个体产生特征性的含IgA 1的抗体复合物，其存款在肾脏中，产生进行性肾损伤。该疾病与促进免疫复合物形成的IgA 1的O-糖基化中的特定致病缺陷相关。与其他免疫介导的疾病相似，IgAN具有复杂的遗传结构。在最近的一项涉及20，574名个体的GWAS中，我们确定了15个IgAN的全基因组显著易感位点。我们的新基因座在疾病发病机制中涉及适应性免疫和先天免疫，并将“肠道伊加产生网络”定义为关键的致病性疾病途径。基于我们的研究结果，我们开发了一个原始的多击发病机制模型，描述了参与疾病发展的顺序步骤和分子候选人。在本申请中，我们建议通过定义参与粘膜伊加反应缺陷调节的额外遗传命中来进一步完善该模型。我们的具体目标是通过定量GWAS检测伊加和半乳糖缺陷型IgA 1（Gd-IgA 1）的血清水平来发现其他IgAN易感基因座。GWAS发现阶段将包括一个由9，707名个体组成的基于多种族人群的高效能队列。新的全基因组重要位点将独立复制，并使用现有数据集和公共资源进行注释。接下来，通过基于网络的综合分析，我们将剖析每个GWAS风险等位基因背后的精确致病机制。我们将使用系统遗传学方法，整合RNA-seq和SNP微阵列数据，以重建IgA 1分泌细胞中的基因调控网络。基于我们的网络分析，我们将定义疾病过程的主要监管机构和关键驱动因素。我们的网络预测将使用实验，计算和遗传方法进行验证。预计这些研究将完善疾病发病机制模型，并将在确定新的治疗干预IgAN的潜在目标是至关重要的。