Genomics of glomerular disease

摘要： 肾小球疾病是继糖尿病和糖尿病之后的第三大最常见的终末期肾病原因。 高血压伊加肾病（IgAN）、局灶节段性肾小球硬化（FSGS）、膜性肾病 (MN)原发性肾小球疾病以微小病变性肾小球疾病（MCD）为主。最近 遗传学研究已经确定了这些疾病的几个遗传位点，并开始确定关键的 参与其发病机制的分子途径。然而，设计良好、动力充足的基因 大多数肾小球疾病类型的相关性研究仍然缺失。此外，该领域还面临着重大挑战， 挑战，包括需要在不同的患者队列中验证新的基因座， 风险等位基因下游的通路及其对临床结果的影响，定义了疾病特异性 和风险等位基因的相互作用，并将其功能后果置于一个连贯的生物网络中。 这样的见解可以转化为临床益处，包括可靠的生物标志物，有效的治疗策略， 筛选和预防，合理选择潜在的治疗靶点。该提案将解决 通过旨在发现、验证和精细定位已知和新型遗传易感基因座来应对上述挑战 基因研究合作。这将包括与阿斯利康和哥伦比亚的开创性伙伴关系 基因组医学研究所将对4,000例肾小球疾病患者进行全基因组测序（WGS） 疾病，包括整个CureGN研究，肾小球疾病患者的最大前瞻性队列。 随后将对另外26，000个病例进行国际荟萃分析和基因验证研究， 活检证实的原发性肾小球疾病接下来，我们将致力于发现精确的致病机制 使用CureGN队列中的系统遗传学研究来支持每个新的遗传基因座。我们将 将遗传数据与血液转录组学研究和临床病理分析相结合，以确定关键的 分子疾病驱动因素及其临床和组织病理学后果。我们的研究将利用 NIDDK在肾小球疾病中的最大投资，以完善分子发病机制，并将在 确定新的治疗干预的目标。

Abstract: Glomerular disorders represent the third-most common cause of end-stage renal disease after diabetes and hypertension. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and minimal change disease (MCD) account for the majority of idiopathic glomerular diseases. Recent genetic studies have identified several genetic loci for these disorders and have begun to identify critical molecular pathways involved in their pathogenesis. However, well-designed and adequately powered genetic association studies are still missing for most glomerular disease types. Moreover, the field is faced with major challenges, including the need to validate the new loci across diverse patient cohorts, understand dysregulated pathways downstream of risk alleles and their consequences on clinical outcomes, define disease-specificity and interactions of risk alleles, and place their functional consequences within a coherent biological network. Such insights can then be translated into clinical benefits, including reliable biomarkers, effective strategies for screening and prevention, and rational selection of potential therapeutic targets. This proposal will address the above challenges by aiming to discover, validate, and fine-map known and novel genetic susceptibility loci by collaborative genetic studies. This will include a pioneering partnership with AstraZeneca and Columbia's Institute for Genomic Medicine to perform whole genome sequencing (WGS) of 4,000 cases of glomerular disease, including the entire CureGN study, the largest prospective cohort of patients with glomerular disorders. This will be followed by international meta-analyses and genetic validation studies in additional 26,000 cases of biopsy-confirmed primary glomerular disorders. Next, we will aim to discover precise pathogenic mechanisms underpinning each of the new genetic loci using systems genetics studies in the CureGN cohort. We will integrate the genetic data with blood transcriptomic studies and clinico-pathologic analyses to identify the key molecular disease drivers and their clinical and histopathologic consequences. Our studies will leverage the largest investment of NIDDK in glomerular diseases to refine the molecular pathogenesis and will be critical in defining targets for novel therapeutic interventions.