Genetics of IgA nephropathy by integrative network-based association studies

 描述(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，也是东亚地区肾功能衰竭的主要原因。受影响的人会形成特有的含有IgA1的抗体复合体，沉积在肾脏中，造成进行性肾脏损伤。这种疾病与免疫球蛋白A1的O-糖基化中的一种特殊的致病缺陷有关，该缺陷促进免疫复合体的形成。与其他免疫介导性疾病类似，IgAN具有复杂的遗传结构。在最近一次涉及20,574名个体的GWA中，我们确定了15个全基因组范围的IgAN显著易感基因座。我们的新基因座涉及获得性免疫和先天免疫在疾病发病机制中的作用，并将“肠道免疫球蛋白A产生网络”定义为关键的致病途径。基于我们的结果，我们开发了一个原始的多点致病模型，该模型描述了参与疾病发展的顺序步骤和候选分子。在这个应用中，我们建议通过定义与黏膜IgA反应的缺陷调控有关的额外的基因点击来进一步完善这一模型。我们的具体目标是通过定量检测血清IgA和半乳糖缺乏性IgA1(Gd-IgA1)水平来发现更多的IgAN易感基因。Gwas的发现阶段将包括一个由9,707人组成的以多种族人口为基础的强大队列。新的全基因组重要基因座将被独立复制，并使用现有的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GWA型风险等位基因背后的精确致病机制。我们将使用整合RNA-seq和SNP微阵列数据的系统遗传学方法来重建IgA1分泌细胞中的基因调控网络。基于我们的网络分析，我们将确定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。这些研究有望完善疾病发病机制模型，并将对确定IgAN新的治疗干预措施的潜在靶点至关重要。

 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.