The Host Genome and the Urinary Microbiome in UTI and GU Structural Defects

UTI 和 GU 结构缺陷中的宿主基因组和泌尿微生物组

• 批准号: 10022308
• 负责人: ALI G GHARAVI
• 金额: $ 23.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022308
• 关键词: 16p11.2; BMP5 gene; Benign; Categories; Child; Childhood; Clinical; Collaborations; Congenital Abnormality; Copy Number Polymorphism; Data; Data Set; Defect; Diagnostic; Disease; Effectiveness; Event; Frequencies; Functional disorder; Funding; Genes; Genetic; Genetic Diseases; Genets; Genome; Genomics; Genotype; Homeostasis; Individual; Internships; Kidney; Longterm Follow-up; Lower urinary tract; Metabolic; Mission; Modeling; Morbidity - disease rate; Mus; Mutation; Outcome; Pathogenesis; Patients; Pattern; Phenotype; Population; Research; Risk stratification; Structural defect; Susceptibility Gene; Symptoms; Syndrome; Testing; Ureter; Urinary Microbiome; Urinary tract; Urinary tract infection; Urology; Urothelium; Use Effectiveness; Variant; Vesico-Ureteral Reflux; WNT5A gene; Work; base; biobank; case control; clinical Diagnosis; clinical care; clinical phenotype; cohort; congenital anomaly; cost; exome; exome sequencing; genetic approach; genetic testing; genome wide association study; genomic locus; high risk; improved; insight; kidney malformation; malformation; microbial genomics; microbiome analysis; mortality; novel; phenome; precision medicine; proband; rare variant; response; risk variant; trait; urinary tract obstruction; variant detection; young adult

PROJECT 1: PROJECT SUMMARY/ABSTRACT Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for a large fraction of congenital malformations and are associated with significant morbidity and mortality in children and young adults. In the previous funding cycle, we have successfully applied genome-wide association study (GWAS), exome sequencing, and copy-number variant (CNV) analysis to identify novel genes and loci for different CAKUT subtypes. These recent findings demonstrate the effectiveness of using genetic approaches to refine clinical diagnoses and determine the pathogenesis of CAKUT subtypes, specifically vesicoureteral reflux (VUR) and its complications. Based on this data and the declining cost of sequencing, which allows for genetic testing to be increasingly incorporated into clinical care, we aim to explore the potential of genetic testing in Urology. To aid in this endeavor, we have developed a curated list of genes involved in lower urinary tract defects and determined the frequency of rare variants in these genes in healthy populations. In this application for Project 1 of the Columbia George M. O’Brien Urology Research Center we will determine the diagnostic utility of exome sequencing for clinical care in patients with simple Urinary Tract Infections (UTIs) and those with lower urinary tract defects with and without UTIs. We will also identify new genes contributing to VUR and UTI by case- control exome-wide association study. Additionally, in collaboration with the Microbial Genomics Biomedical Core, we will examine genotype-phenotype correlations, including analysis of the urinary microbiome in patients with different mutations and structural defects. Furthermore, we will perform rare variant burden tests to identify new genes predisposing to UTI and VUR, and examine the implication of these genetic discoveries to detect novel additional clinical associations with PheWAS and microbiome analysis based on genotype data. With these aims, we will fulfill the larger mission of the Columbia O’Brien Center by investigating the genetic, cellular and metabolic basis of UTI as well provide new insight into the pathogenesis of disorders highly relevant to the field of benign urology while facilitating the introduction of Precision Medicine into the practice of Pediatric Urology.

项目 1：项目摘要/摘要 先天性肾脏和尿路异常 (CAKUT) 占先天性畸形的很大一部分 畸形，并与儿童和年轻人的显着发病率和死亡率相关。 上一个资助周期，我们已经成功应用了全基因组关联研究（GWAS）、外显子组 测序和拷贝数变异 (CNV) 分析，以确定不同 CAKUT 的新基因和基因座 这些最近的发现证明了使用遗传方法来改善临床的有效性。 诊断并确定 CAKUT 亚型的发病机制，特别是膀胱输尿管反流 (VUR) 及其 基于这些数据和测序成本的下降，基因检测成为可能。 我们的目标是探索基因检测在泌尿外科领域的潜力，以帮助其越来越多地融入临床护理。 在这一努力中，我们制定了一份与下尿路缺陷有关的基因的精选清单， 在项目 1 的本申请中确定了这些基因中罕见变异的频率。 哥伦比亚乔治·M·奥布莱恩泌尿学研究中心的我们将确定外显子组的诊断效用 单纯性尿路感染 (UTI) 和低尿路感染患者的临床护理测序 我们还将根据病例确定导致 VUR 和 UTI 的新基因。 此外，与微生物基因组学生物医学合作进行控制全外显子组关联研究。 核心，我们将检查基因型-表型相关性，包括分析尿微生物组 此外，我们将进行罕见变异负荷测试。 识别易患 UTI 和 VUR 的新基因，并检验这些基因发现的含义 检测与 PheWAS 和基于基因型数据的微生物组分析的新的额外临床关联。 有了这些目标，我们将通过研究遗传、 尿路感染的细胞和代谢基础也为疾病的高度发病机制提供了新的见解 与良性泌尿外科领域相关，同时促进将精准医学引入实践 小儿泌尿外科。