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

项目1：项目总结/摘要 先天性肾脏和泌尿道异常（CAKUT）占先天性肾脏和泌尿道畸形的很大一部分。 畸形，并与儿童和青年的发病率和死亡率显著相关。在 上一个资助周期，我们已经成功地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，以鉴定不同CAKUT的新基因和基因座 亚型这些最近的发现证明了使用遗传方法来改善临床 诊断和确定CAKUT亚型的发病机制，特别是膀胱输尿管反流（VUR）及其 并发症基于这些数据和测序成本的下降，这使得基因检测可以 随着基因检测越来越多地被纳入临床护理，我们的目标是探索基因检测在泌尿科的潜力。以帮助 在这项奋进中，我们已经开发了一个与下尿路缺陷有关的基因的精选列表， 确定了这些基因在健康人群中罕见变异的频率。在此项目1的申请中 哥伦比亚乔治M.奥布莱恩泌尿学研究中心，我们将确定外显子组的诊断效用 单纯性尿路感染（UTI）和下尿路感染患者的临床护理顺序 有或无尿路感染的尿道缺损。我们还将通过病例确定导致VUR和UTI的新基因- 控制全外显子组关联研究。此外，与微生物基因组学生物医学合作， 核心，我们将检查基因型-表型相关性，包括分析尿微生物组， 有不同突变和结构缺陷的患者。此外，我们将进行罕见的变异负荷测试 鉴定新的易患UTI和VUR的基因，并研究这些基因发现的意义 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，我们将完成哥伦比亚奥布莱恩中心更大的使命，研究遗传， UTI的细胞和代谢基础以及提供了新的见解疾病的发病机制高度 与良性泌尿外科领域相关，同时促进将精准医学引入到 小儿泌尿科。

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.