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.

项目摘要 糖尿病性肾病（DN）是糖尿病的复杂，异质并发症，其特征是 渐进的肾脏下降。虽然已知遗传因素有助于DN的敏感性，但Dospite强烈 努力，鉴定其风险背后的变体受到了挑战，这主要是由于贫困的稀缺性 旨在研究快速肾脏下降的遗传基础的表征。克服这一点 瓶颈，我们已经开发了一种创新的基于家庭的方法来加速DN的基因发现，该方法是 包含电子的集成无与伦比的资源，包括犹他州糖尿病数据库（UDDB） 犹他州人口数据库的350,000多名糖尿病患者的病历数据，这是一个独特的 基于人群的家谱资源，其中包含家庭历史和人口统计数据1400万 个体和座座生物座席，一种大型生物座，包含147,000的生物测量 UDDB中的患者。使用这些资源，我们已经建立了世界上最大，良好的之一 表征了糖尿病患者的同类群体，肾脏下降的快速进展，鉴定出> 450个大的糖尿病患者 多代谱系富含DN的关键特征。作为最近的一项试点研究的一部分，应用了我们 方法，我们确定了2个基因（ADIPOQ和FRAS1）中的假定致病变体 已知会导致DN。这些强大的初步发现突出了基于家庭的遗传学的力量 发现有助于快速肾脏下降和DN的新型基因。我们认为这些研究只是 “冰山一角”和其他诱发的基因和途径仍有待发现。进一步 提出这项研究，我们将1）定义adipoq和adipoq的病理生理机制 FRAS1通过i）检查ADIPOQ突变对DN家族的肾脏下降的快速发展 使用一般编辑的小鼠（携带人类突变的小鼠，肾脏下降和DN发育 在高风险的谱系中，已经产生），ii）检查FRAS1突变在肾脏上的作用 使用一般编辑的小鼠的衰落和DN发育。 2）建立一个综合编码目录 DN家族的变化富含肾脏下降的快速进展，i）优先级 使用犹他大学开发的创新工具，以快速肾脏下降，并确定选择 这些家族的个人以优化基于WES的基因发现和ii）进行基于WES的基因 在新确定的高风险谱系中发现，富含肾脏下降。 3）评估因果 在富含肾脏下降快速进展的DN家族中鉴定出的遗传变异之间的关系 i）优先考虑使用WES发现的候选基因来识别最有前途的候选基因 使用统计和生物学证据以及ii）进行体外和体内测定的候选者进行研究 优先候选基因的生物学影响。合并，拟议的研究将显着 促进我们对DN和快速肾脏下降的遗传学和生物学的理解。