Genetic Variations and Development of Vesicoureteral Reflux and Sequelae

描述（由申请方提供）：膀胱输尿管反流（VUR）肾病是儿童终末期肾病的第四大病因，影响所有儿童的0.4-1.8%。研究人员已经开始确定导致VUR的肾脏发育基因缺陷。然而，反流发展以外的因素可能发挥重要作用，因为许多反流患者完全无症状，而其他患者通常在复发性尿路感染（UTI）后出现肾瘢痕、高血压和慢性肾脏疾病。这项建议的长期目标是确定遗传学在VUR及其相关并发症的发展中所起的确切作用。最近，研究人员已经开始确定强大的宿主防御机制，特别是抗微生物肽（AMP），它可以防止UTI。最近，由于DNA结构改变，如拷贝数变异（CNVs），编码AMP的基因发生了改变。DNA拷贝数的这些变化可以对基因剂量产生深远的影响，并且DNA拷贝数的改变在疾病易感性或抗性中起关键作用。自从他们最近的发现以来，AMP中的CNV与克罗恩病的易感性有关。与克罗恩病相关的肠道AMP类似，尿路中AMP的存在表明AMP CNV也有助于UTI易感性。我们假设VUR患者复发性UTI和随后的肾瘢痕形成的主要风险是抗菌肽和趋化因子基因的基因剂量改变，这可能与肾脏发育缺陷有关。为此，我们将使用全基因组CNV阵列鉴定和比较具有和不具有复发性UTI的VUR患者与年龄和性别匹配的对照中候选先天免疫和肾脏发育基因CNV的流行率（具体目标1）。这将通过分析入组RIVUR研究（一项分析VUR儿童抗生素预防的随机对照试验）的患者的DNA来完成。在具体目标2中，我们将对选定的患者子集进行外显子序列捕获，以寻找对先天免疫和肾脏发育至关重要的基因突变。最后，在特定目标3中，我们将对RIVUR研究的基因组数据和临床数据进行复杂的生物信息学分析。这些研究将导致新的信息的作用，遗传变异的发展VUR及其后遗症。此外，它们将为识别“高危”患者和免疫调节治疗靶点提供基础。 公共卫生相关性：膀胱输尿管反流，或尿液从膀胱到肾脏的异常反流，是一种常见的儿童疾病，影响所有儿童的1%，但遗传原因尚不清楚。此外，只有一些膀胱输尿管反流患者会发生尿路感染，甚至更少的患者会因为这些感染而出现肾脏问题。一些研究表明，负责蛋白质的DNA的改变，蛋白质作为我们身体的抗生素可能会使一些人容易感染。通过确定抗生素蛋白在泌尿系统防御感染中的作用，我们将确定这些抗生素蛋白是否可用于识别或治疗尿路感染风险人群。此外，我们将调查膀胱输尿管反流的潜在遗传原因。

DESCRIPTION (provided by applicant): Vesicoureteral reflux (VUR) nephropathy is the 4th leading etiology of end stage renal disease in children and affects 0.4-1.8% of all children. Researchers have begun to identify defects in renal development genes which result in VUR. However, factors other than the development of reflux might play an important role since many reflux patients are entirely asymptomatic while others develop renal scarring, hypertension and chronic kidney disease, usually following recurrent urinary tract infections (UTIs). The long-term objective of this proposal is to determine the precise role that genetics plays both in the development of VUR and its associated complications. Recently, investigators have begun to identify formidable host defense mechanisms, notably antimicrobial peptides (AMPs), which protect against UTIs. Recently, alterations in genes encoding AMPs have been reported due DNA structural alterations such as copy number variations (CNVs). These changes in DNA copy number can have profound effects on gene dosage, and alterations in DNA copy number play a key role in disease susceptibility or resistance. Since their recent discovery, CNVs in AMPs have been associated with susceptibility to Crohn's disease. The presence of AMPs in the urinary tract, similar the intestinal AMPs relevant to Crohns disease, suggests that AMP CNVs also contribute to UTI susceptibility. We hypothesize that the primary risk for recurrent UTI and subsequent renal scarring in VUR patients is altered gene dosage of antimicrobial peptide and chemokine genes, which may occur in conjunction with defects in renal development. To this end we will identify and compare the prevalence of candidate innate immunity and kidney development gene CNVs in patients with VUR with and without recurrent UTIs versus age and gender-matched controls using genome- wide CNV arrays (Specific Aim 1). This will be accomplished by analyzing DNA from patients enrolled in the RIVUR study (a randomized control trial analyzing antibiotic prophylaxis in children with VUR). In Specific Aim 2, we will perform exome sequence capture on a selected subset of patients to look for mutations in genes critical to innate immunity and kidney development. Finally, in Specific Aim 3, we will perform a sophisticated bioinformatic analysis of the genomic data and clinical data from the RIVUR study. These studies will result in novel information regarding the role of genetic variations in the development of VUR and its sequelae. Furthermore, they will provide the basis to identify "at risk" patients and therapeutic targets for immunomodulation. PUBLIC HEALTH RELEVANCE: Vesicoureteral reflux, or abnormal backflow of urine from the bladder to the kidneys, is a common childhood disease affecting 1% of all children, yet the genetic cause is unknown. Furthermore, only some patients with vesicoureteral reflux develop urinary tract infections and even fewer develop kidney problems because of these infections. Some research has suggested alterations in the DNA responsible for proteins, which function as our bodies' antibiotics might make some individuals prone to infections. By determining the role of antibiotic proteins in the urinary system's defense against infection, we will determine if these antibiotic proteins can be used to identify or treat people at risk for urinary tract infections. Also, we will investigate potential genetic causes of vesicoureteral reflux.