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: 10392503
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 65.38万
• 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/10392503
• 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.

项目概要 糖尿病肾病（DN）是一种复杂的、异质性的糖尿病并发症，其特点是 进行性肾功能减退。尽管已知遗传因素会导致 DN 易感性​​，尽管 尽管付出了努力，识别导致其风险的变异一直具有挑战性，这主要是由于缺乏良好的 旨在研究肾功能快速衰退的遗传基础的特征队列。为了克服这个 瓶颈，我们开发了一种基于家族的创新方法来加速 DN 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)，其中包含电子版 犹他州人口数据库包含超过 350,000 名糖尿病患者的医疗记录数据，这是一个独特的数据库 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，以及山间生物样本库，这是一个包含 147,000 个生物样本的大型生物样本库 UDDb 中的患者。利用这些资源，我们建立了世界上最大、最完善的系统之一 对肾功能衰退快速进展的糖尿病患者队列进行了特征分析，并确定了超过 450 名大、 多代谱系丰富了 DN 的这一关键特征。作为最近一项试点研究的一部分，应用我们的 通过这种方法，我们发现了 2 个基因（ADIPOQ 和 FRAS1）中先前未发现的假定致病变异 已知对 DN 有贡献。这些强有力的初步发现凸显了基于家族的遗传学的力量 发现导致肾功能快速衰退和 DN 的新基因。我们相信这些研究只是 “冰山一角”以及其他易感基因和途径仍有待发现。为了进一步 推进这项研究，我们将 1) 定义 ADIPOQ 和 FRAS1 通过 i) 检查 ADIPOQ 突变对 DN 家族肾衰的快速进展的影响 使用基因编辑小鼠（携带已鉴定的人类突变的小鼠）进行肾功能衰退和 DN 发展 已生成高风险谱系）和 ii）检查 FRAS1 突变对肾脏的作用 使用基因编辑小鼠进行的衰退和 DN 发展。 2）建立全面的编码目录 通过 i) 优先考虑高风险谱系，DN 家族的变异丰富了肾功能衰退的快速进展 使用犹他大学开发的创新工具，并确定精选的药物，可促进肾功能快速衰退 来自这些家庭的个体优化基于 WES 的基因发现，并 ii) 执行基于 WES 的基因 在新发现的高风险谱系中发现了肾功能快速衰退的现象。 3）评估因果关系 DN 家族中发现的遗传变异之间的关系，这些变异导致肾功能衰退快速进展 i) 优先考虑使用 WES 发现的候选基因，以确定最有希望的基因 候选人使用统计和生物学证据，以及 ii) 进行体外和体内测定以进行调查 优先候选基因的生物学影响。结合起来，拟议的研究将显着 增进我们对 DN 的遗传学和生物学以及肾功能快速衰退的理解。