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: 10622508
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 65.31万
• 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/10622508
• 关键词: Acceleration; 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; Deterioration; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dominant-Negative Mutation; Extracellular Matrix Proteins; Family; Fraser syndrome; Genealogy; Genes; Genetic; Genetic study; Goals; Hormones; Human; In Vitro; Individual; Kidney; Kidney Diseases; Learning; 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; biobank; candidate identification; cohort; conditional knockout; design; diabetic patient; drug discovery; epidemiology study; exome sequencing; gene discovery; genetic architecture; 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 糖尿病肾病（DN）是糖尿病的一种复杂的异质性并发症，其特征在于： 进行性肾功能下降虽然已知遗传因素有助于DN的易感性，尽管强烈 努力，识别其风险基础的变体一直具有挑战性，主要是由于缺乏良好的 特征性队列，旨在研究快速肾功能下降的遗传基础。为了克服这个 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， 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 犹他州人口数据库是一个独特的， 基于人口的家谱资源，包含1400万人的家族历史和人口统计数据 和山间生物储存库，一个大型生物储存库，包含147，000个生物标本 患者在UDDb。利用这些资源，我们建立了世界上最大的- 具有肾功能下降快速进展的糖尿病患者的特征队列，并确定了>450个大的， 多代谱系丰富了DN的这一关键特征。作为最近试点研究的一部分， 方法，我们确定了2个基因（ADIPOQ和FRAS 1）中的假定致病变异体， 已知会导致DN这些强有力的初步发现突出了以家庭为基础的遗传学的力量， 发现导致肾功能快速下降和DN的新基因。我们相信这些研究只是 “冰山一角”，更多的易感基因和途径仍有待发现。进一步 为了推进这项研究，我们将1）确定ADIPOQ和 FRAS 1通过以下方式影响DN家族中肾功能下降的快速进展：i）检查ADIPOQ突变对 使用基因编辑小鼠（携带人类突变的小鼠， 已经产生了高风险谱系）和ii）检查FRAS 1突变对肾功能的作用， 使用基因编辑的小鼠进行的下降和DN发展。2)建立全面的编码目录 通过i）优先考虑高风险家系，丰富DN家族中肾功能下降快速进展的变异 使用犹他州大学开发的创新工具， ii）对来自这些家族的个体进行基于WES的基因发现，以优化基于WES的基因发现，以及 在新发现的高风险家系中发现了快速肾功能下降。3)评估因果关系 在DN家族中鉴定的遗传变异与肾功能快速下降的关系 i）优先考虑使用WES发现的候选基因，以确定最有希望的 使用统计学和生物学证据的候选物和ii）进行体外和体内测定以研究 优先候选基因的生物学影响。结合起来，拟议的研究将大大 促进我们对DN和肾脏快速衰退的遗传学和生物学的了解。