Evaluation of germline mutations associated with risk of nephrolithiasis

与肾结石风险相关的种系突变的评估

• 批准号: 8678066
• 负责人: William Haley
• 金额: $ 23.48万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678066
• 关键词: Accounting; Acute; Affect; Age; Alanine-glyoxylate aminotransferase; Aldehyde-Lyases; American; Back; Blood; Calcium; Calcium Oxalate; Calculi; Case-Control Studies; Characteristics; Chloride Channels; Chronic Kidney Failure; Clinic; Clinical Data; Cystinuria; Data; Development; Disease; Early Diagnosis; End stage renal failure; Enrollment; Environmental Risk Factor; Etiology; Evaluation; Family history of; Flank Pain; Florida; Forms Controls; Frequencies; Gene Mutation; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic screening method; Genomic DNA; Germ-Line Mutation; Hereditary Disease; Hospitalization; Hydroxypyruvate reductase; Hypertension; Incidence; Individual; Inherited; Intervention; Investigation; Kidney; Kidney Calculi; Kidney Failure; Life Style; Link; Literature; Morbidity - disease rate; Mutate; Mutation; Myocardial Infarction; Nature; Nausea and Vomiting; Nephrolithiasis; Operative Surgical Procedures; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Population Control; Predisposing Factor; Prevalence; Prevention; Prevention strategy; Public Health; Publishing; RNA; Race; Recurrence; Registries; Relative (related person); Reporting; Risk; Risk Factors; Role; Sampling; Symptoms; Treatment Protocols; United States; Urine; Work; adenine phosphoribosyltransferase; alpha ketoglutarate; base; clinical risk; cohort; cost; disorder risk; early childhood; gene panel; genetic risk factor; genetic variant; glyoxylate reductase; high risk; inositol-1,4,5-trisphosphate 5-phosphatase; loss of function; meetings; novel; patient population; public health relevance; screening; sex; socioeconomics; treatment strategy; urolithiasis; urologic; voltage

PROJECT SUMMARY/ABSTRACT Nephrolithiasis occurs in approximately 1 in 10 individuals in the United States with increasing prevalence noted over the past three decades. Recurrence is common occurring in around 50% of these patients, many of whom require surgical intervention. An estimated 5-6 billion dollars a year is spent on the treatment of kidney stones. Symptoms of kidney stones include flank pain, blood in the urine, nausea and vomiting. Beyond acute attacks associated with considerable morbidity and cost, recent reports have identified associations between kidney stone formation and increased risk for the development of hypertension, chronic kidney disease, end stage renal disease and myocardial infarction. Therefore, nephrolithiasis not only impacts socioeconomics but also has broader public health implication. Genetic and environmental risk factors are both linked to nephrolithiasis with about 40% of patients presenting with kidney stones having at least one relative who is also a stone former. Genetic variants causative of monogenic forms of nephrolithiasis have been well defined. However the frequency of monogenic mutations and their presence as predisposing factors of disease is poorly understood within the idiopathic stone forming population. We have identified that heterozygous mutations of HOGA1, a gene associated with the onset of primary hyperoxularia Type III, are present within idiopathic stone formers and absent in matched controls. These findings suggest that the presence of these mutations could be indicative of increased risk for kidney stone formation within these patients. We therefore propose to; Aim 1: Validate and expand our previous studies to define that genetic variations of HOGA1 are a predisposing factor for idiopathic calcium-oxalate stone formation, and Aim 2: Mutational analysis of genes involved in kidney stone formation for determination of genetics of risk. These studies will identify the frequency of known genetic variants associated with monogenic forms of nephrolithiasis within idiopathic stone formers and associate their presence with heightened risk. Patient genomic DNA, blood, clinical data and risk data are available from the Mayo Clinic Kidney Stone Registry. Genomic DNA and RNA will be assessed for mutations within HOGA1 and their significance as predisposing factors for disease evaluated through statistical analysis and compared to environmental risk factors. Furthermore, genetic variants within AGXT, GRHPR, CLCN5, OCRL1, SLC3A1, SLC7A9, and APRT will be analyzed for frequency in idiopathic nephrolithiasis patients and control populations to determine their role as predictive genetic markers for idiopathic disease risk. This proposed study has the potential to identify genetic variants that are predisposing factors for idiopathic kidney stone formation and are predictive of disease risk. These studies have relevance to personalized treatment regimens for disease intervention, targeted prevention of reoccurrence and development of genetic tests for early diagnosis of patients at higher risk of idiopathic nephrolithiasis.

项目摘要/摘要 肾结石病在美国大约10个人中发生，患病率增加 在过去的三十年中注意到。这些患者中约有50％发生复发是常见的 需要手术干预的人。估计每年花费5-6亿美元用于肾脏的治疗 石头。肾结石的症状包括侧面疼痛，尿液中的血液，恶心和呕吐。超越敏锐 攻击与相当大的发病率和成本相关，最近的报告确定了 肾结石的形成和增加高血压，慢性肾脏疾病的风险增加 阶段肾脏疾病和心肌梗塞。因此，肾物石病不仅会影响社会经济学，而且会影响 还具有更广泛的公共卫生含义。遗传和环境风险因素都与 大约40％患有至少一个亲戚的肾结石的患者中，大约40％的肾结石病 也是一块石头。肾疾病的单基因形式的遗传变异已得到很好的定义。 但是，单基因突变的频率及其作为疾病诱发因素的存在很差 在特发性石头形成人群中被理解。 我们已经确定了HOGA1的杂合突变，该基因与原代发作有关 III型高氧型，存在于特发性石材形成器中，并且在匹配的对照中不存在。这些 调查结果表明，这些突变的存在可能表明肾结石的风险增加 这些患者形成。因此，我们建议；目标1：验证并将我们以前的研究扩展到 定义hoga1的遗传变异是特发性钙石材的诱发因素 形成，目标2：用于确定肾结石形成的基因的突变分析 风险遗传学。这些研究将确定与单基因相关的已知遗传变异的频率 特发岩石中的肾结石病的形式，并将其存在与风险增加相关联。 患者基因组DNA，血液，临床数据和风险数据可从Mayo诊所肾结石获得 注册表。基因组DNA和RNA将评估HOGA1内的突变及其意义 通过统计分析评估的疾病因素的诱发因素，并将其与环境风险进行比较 因素。此外，AGXT，GRHPR，CLCN5，OCRL1，SLC3A1，SLC7A9和APRT中的遗传变异将会 分析特发性肾石岩病患者和对照人群的频率以确定其作用 作为特发性疾病风险的预测遗传标记。 这项拟议的研究具有鉴定遗传变异的潜力，这是易感性因素 特发性肾结石的形成，可以预测疾病的风险。这些研究与 个性化治疗方案，用于疾病干预，有针对性的预防再发生和 开发基因检测，以早期诊断为特发性肾石岩症风险较高的患者。