Genetic and Functional Analysis of Rapid Renal Decline in Diabetes: A Family-based Approach to Accelerate Gene Discovery

糖尿病肾病快速衰退的遗传和功能分析：加速基因发现的基于家族的方法

• 批准号: 10186273
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 65.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10186273
• 关键词: Adipose tissue; Affect; Anti-Inflammatory Agents; Antidiabetic Drugs; Apoptotic; Area; Biological; Biological Assay; Biology; Candidate Disease Gene; Catalogs; Clinical; Code; Complex; Complications of Diabetes Mellitus; Computerized Medical Record; Data; Databases; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dominant-Negative Mutation; Extracellular Matrix Proteins; Family; Fraser syndrome; Genealogy; Genes; Genetic; Goals; Hormones; Human; In Vitro; Individual; Kidney; Kidney Diseases; Longitudinal Studies; Mus; Mutation; Pathway interactions; Patients; Phenotype; Pilot Projects; Population Database; Predisposition; Property; Proteins; Publishing; Recording of previous events; Renal function; Reporting; Research; Resources; Risk; Role; Shapes; Susceptibility Gene; Universities; Utah; Variant; adiponectin; base; biobank; cohort; conditional knockout; design; diabetic patient; drug discovery; exome sequencing; gene discovery; genetic architecture; genetic epidemiology; genetic pedigree; genetic variant; genome wide association study; genome-wide; high risk; improved; in vivo; innovation; insight; link protein; novel; population based; prevent; tool

PROJECT SUMMARY Diabetic nephropathy (DN) is a complex, heterogeneous complication of diabetes that is characterized by progressive renal decline. While genetic factors are known to contribute to DN susceptibility, despite intense effort, the identification of variants that underlie its risk has been challenging, largely due to the scarcity of well- characterized cohorts designed to investigate the genetic basis of rapid renal decline. To overcome this bottleneck, we’ve developed an innovative family-based approach to accelerate gene discovery in DN that integrates unparalleled resources, including the Utah Diabetes Database (UDDb), which contains electronic medical record data for more than 350,000 diabetic patients, the Utah Population Database, a unique population-based genealogy resource containing family histories and demographic data for 14 million individuals, and the Intermountain Biorepository, a large biorepository containing biospecimens for 147,000 patients in the UDDb. Using these resources, we’ve established one of the world’s largest and well- characterized cohorts of diabetic patients with rapid progression of renal decline and identified >450 large, multigenerational pedigrees enriched for this key feature of DN. As part of a recent pilot study applying our approach, we identified putative disease-causing variants in 2 genes (ADIPOQ and FRAS1) not previously known to contribute to DN. These strong preliminary findings highlight the power of family-based genetics to discover novel genes that contribute to rapid renal decline and DN. We believe that these studies are just the ‘tip of the iceberg’ and that additional predisposing genes and pathways remain to be discovered. To further advance this research, we will 1) define the pathophysiological mechanisms through which ADIPOQ and FRAS1 affect rapid progression of renal decline in DN families by i) examining the role of ADIPOQ mutation on renal decline and DN development using genetically edited mice (mice carrying the human mutation identified in a high-risk pedigree have already been generated) and ii) examining the role of FRAS1 mutation on renal decline and DN development using genetically edited mice. 2) Establish a comprehensive catalog of coding variation in DN families enriched for rapid progression of renal decline by i) prioritizing high-risk pedigrees enriched for rapid renal decline using innovative tools developed at the University of Utah and identifying select individuals from these families to optimize WES-based gene discovery and ii) performing WES-based gene discovery in newly identified high-risk pedigrees enriched for rapid renal decline. 3) Evaluate the causal relationship between genetic variants identified in DN families enriched for rapid progression of renal decline and rapid renal decline by i) prioritizing candidate genes discovered using WES to identify the most promising candidates using statistical and biological evidence and ii) performing in vitro and in vivo assays to investigate the biological impact of prioritized candidate genes. Combined, the proposed research will significantly advance our understanding of the genetics and biology of DN and rapid renal decline.

项目总结 糖尿病肾病是一种复杂的、异质性的糖尿病并发症，其特点是 进行性肾功能衰退。虽然已知遗传因素有助于糖尿病肾病的易感性，但 努力，识别其潜在风险的变种一直是具有挑战性的，主要是由于井- 旨在研究肾功能快速衰退的遗传学基础的特化队列研究。要克服这一点 瓶颈，我们开发了一种创新的基于家庭的方法来加速糖尿病肾病的基因发现 整合了无与伦比的资源，包括犹他州糖尿病数据库(UDDb)，其中包含电子产品 超过350,000名糖尿病患者的医疗记录数据，犹他州人口数据库，一个独特的 基于人口的家谱资源，包含1400万人的家族史和人口数据 个人，以及山间生物库，这是一个包含147,000个生物检疫的大型生物储存库 UDDB中的患者。利用这些资源，我们已经建立了世界上最大和最好的之一- 描述了糖尿病患者的特点，这些患者肾功能迅速恶化，并发现&gt；450大， 多代人的家谱丰富了糖尿病肾病的这一关键特征。作为最近一项试点研究的一部分，我们应用了 方法，我们在以前没有发现的两个基因(ADIPOQ和FRAS1)中发现了可能的致病变异 已知对糖尿病肾病有贡献。这些强有力的初步发现突出了以家族为基础的遗传学对 发现导致肾脏快速衰退和糖尿病肾病的新基因。我们相信这些研究只是 “冰山一角”，还有其他致病基因和致病途径有待发现。为了进一步 为了推进这项研究，我们将1)确定ADIPOQ和ADIPOQ通过 FRAS1通过I)检测ADIPOQ突变在糖尿病肾病家族中的作用影响糖尿病肾病家系中肾功能衰退的快速进展 使用基因编辑的小鼠(携带人类突变的小鼠)的肾脏衰退和糖尿病肾病的发展 在高危家系中已经产生)和ii)检查FRAS1突变对肾脏的作用 使用基因编辑的小鼠进行衰退和糖尿病肾病的发展。2)建立全面的编码目录 通过优先选择高危家系使肾衰竭快速进展的糖尿病肾病家系发生变异 使用犹他大学开发的创新工具和识别SELECT 来自这些家庭的个体以优化基于WES的基因发现和II)执行基于WES的基因 在新发现的肾功能快速衰退的高危家系中发现。3)评估原因 肾衰快速进展致富的糖尿病肾病家系中发现的基因变异之间的关系 通过i)优先使用WES发现的候选基因来识别最有希望的 候选人使用统计和生物学证据和II)进行体外和体内测试以调查 优先候选基因的生物学影响。总而言之，拟议的研究将显著 促进我们对糖尿病肾病和快速肾衰的遗传学和生物学的理解。