Genetic determinants of urine lithogenicity

尿液成石性的遗传决定因素

• 批准号: 7920691
• 负责人: John C Lieske
• 金额: $ 10.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920691
• 关键词: Accounting; Address; Adenylate Cyclase; Affect; Alkalies; Anions; Arterial Disorder; Biological Markers; Blood Pressure; Blood Vessels; Calcium; Calcium Oxalate; Calcium-Sensing Receptors; Calculi; Candidate Disease Gene; Cardiac; Cerebrum; Chloride Channels; Citrates; Collection; Communities; County; Crystallization; Data; Diabetes Mellitus; Diet; Dietary Factors; Dietary intake; Environment; Environmental Risk Factor; Epidemiologist; Excretory function; Family; Food; Formates; Frequencies; General Population; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomics; Genotype; Goals; Grant; Heritability; Hour; Hyperoxaluria; Hypertension; Intake; Kidney Calculi; Knowledge; Lead; Lysine; Maps; Measurement; Measures; Mediator of activation protein; Methods; Nephrolithiasis; Organ; Oxalates; Pain; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peripheral; Phenotype; Population; Population Study; Potassium; Proteins; Questionnaires; Research Infrastructure; Research Personnel; Resources; Risk; Risk Factors; Scientist; Sodium; Translating; UMOD gene; United States; Urate; Uric Acid; Urine; Variant; Vitamin D3 Receptor; absorption; base; bikunin; cofactor; cohort; cost; diaries; dietary control; economic cost; experience; gastrointestinal; gene interaction; genetic association; genetic epidemiology; genetic linkage; genetic linkage analysis; genetic risk factor; genome-wide linkage; hypercalciuria; improved; indexing; inhibitor/antagonist; insight; macromolecule; member; multidisciplinary; osteopontin; population based; prothrombin fragment 1; trait; treatment strategy; urinary

DESCRIPTION (provided by applicant): Nephrolithiasis (NL) affects up to 10% of the population producing significant pain and suffering, as well as great economic costs (up to $5.3 billion per year in the United States). Treatment strategies are imperfect and have not improved substantially over the last 30 years, in part because the key pathogenic steps remain poorly defined. Therefore, we have assembled a multidisciplinary team to define genetic risk factors for NL. A key and unique resource of our application is the Rochester, MN cohort of the Genetic Epidemiology Network of Arteriopathy (GENOA), which has conducted genome-wide linkage and association studies to identify genes influencing blood pressure and end-organ complications of hypertension (HTN). Members of the well-characterized GENOA cohort will be phenotyped for kidney stone risk via 24-hour urine measurements of lithogenic factors including calcium, oxalate, citrate, and uric acid excretion, as well as overall crystallization inhibition (upper limit of metastability, ULM). Extensive pre-existing genotyping data of the GENOA cohort will be analyzed via genome-wide linkage, together with selected NL candidate gene associations (vitamin D receptor, soluble adenylate cyclase, intracellular protease with no lysine WNK4, chloride channel CLCN5, calcium sensing receptor, urinary prothrombin fragment 1, urate anion transporter 1, oxalate-formate exchanger Slc26a6, Tamm-Horsfall Protein, osteopontin, and bikunin). These studies will determine if specific loci or candidate genes associate with corresponding urinary lithogenic factors (e.g., 24-hr excretion of calcium, oxalate, citrate, or uric acid; ULM). Genetic linkage and association analyses will control for diet and other environmental factors, and assess potential gene-environment and gene-gene interactions. These will be the first studies to assess genetic determinants of urinary lithogenic factors other than calcium in a population-based cohort, taking into account the important covariate of diet. Specific Aims are: Aim #1: Use variance component methods for univariate and multivariate quantitative trait linkage analyses to determine if urinary lithogenic measures (24-hr excretion of calcium, oxalate, citrate, and uric acid; crystallization inhibition) map to specific genomic regions in the GENOA cohort, controlling for dietary factors; Aim #2: Use family-based association methods to determine if urinary lithogenic measures (24-hr excretion of calcium, oxalate, citrate, and uric acid; crystallization inhibition) associate with polymorphisms in selected candidate genes in the GENOA cohort, adjusting for dietary factors, and determine if gene-environment and gene-gene interactions are present. Our goal is to establish genetic associations with urinary NL risk factors in a community- based cohort. The vast experience and infrastructure of GENOA investigators and use of pre-existing genotyping data will allow completion of these studies at a fraction of the cost otherwise required. Results should provide new insight into the pathogenesis of NL, and may lead to identification of new potential treatment targets.Kidney stones are common, and it is known that specific changes in the urinary composition are important risk factors, for example higher than normal calcium excretion. However, the genetic factors that cause these urinary changes have not been well defined. Therefore, in this grant we determine if specific genetic loci or candidate genes associate with kidney stone risk factors in a well-studied population for whom vast amounts of genetic data are already available, the Olmsted County GENOA cohort.

描述（由申请人提供）：肾结石 (NL) 影响多达 10% 的人口，带来严重的疼痛和痛苦，以及巨大的经济损失（在美国每年高达 53 亿美元）。治疗策略并不完善，在过去 30 年里没有得到实质性改善，部分原因是关键的致病步骤仍然不明确。因此，我们组建了一个多学科团队来定义 NL 的遗传风险因素。我们应用程序的一个关键且独特的资源是动脉病遗传流行病学网络 (GENOA) 的明尼苏达州罗彻斯特队列，该队列进行了全基因组连锁和关联研究，以确定影响血压和高血压终末器官并发症 (HTN) 的基因。 ）。通过 24 小时尿液测量包括钙、草酸盐、柠檬酸盐和尿酸排泄在内的成石因素以及整体结晶抑制（亚稳定性上限，ULM），对充分表征的 GENOA 队列成员进行肾结石风险表型分析。将通过全基因组连锁分析 GENOA 队列的大量预先存在的基因分型数据，以及选定的 NL 候选基因关联（维生素 D 受体、可溶性腺苷酸环化酶、不含赖氨酸的细胞内蛋白酶 WNK4、氯离子通道 CLCN5、钙传感受体、尿凝血酶原片段 1、尿酸盐阴离子转运蛋白 1、草酸盐-甲酸交换器 Slc26a6、 Tamm-Horsfall 蛋白、骨桥蛋白和 bikunin）。这些研究将确定特定位点或候选基因是否与相应的尿路成石因素（例如钙、草酸盐、柠檬酸盐或尿酸的 24 小时排泄；ULM）相关。遗传连锁和关联分析将控制饮食和其他环境因素，并评估潜在的基因-环境和基因-基因相互作用。这些将是第一个在基于人群的队列中评估除钙以外的尿路成石因素的遗传决定因素的研究，同时考虑到饮食的重要协变量。具体目标是： 目标#1：使用方差分量方法进行单变量和多变量数量性状连锁分析，以确定尿液成石指标（钙、草酸盐、柠檬酸盐和尿酸的 24 小时排泄；结晶抑制）是否映射到特定基因组区域在热那亚队列中，控制饮食因素；目标#2：使用基于家族的关联方法来确定尿结石测量值（钙、草酸盐、柠檬酸盐和尿酸的 24 小时排泄；结晶抑制）是否与 GENOA 队列中选定候选基因的多态性相关，并根据饮食进行调整因素，并确定是否存在基因-环境和基因-基因相互作用。我们的目标是在社区队列中建立与泌尿 NL 危险因素的遗传关联。热那亚研究人员的丰富经验和基础设施以及对现有基因分型数据的使用将使这些研究能够以其他方式所需成本的一小部分完成。结果应该为 NL 的发病机制提供新的见解，并可能导致确定新的潜在治疗靶点。肾结石很常见，众所周知，尿液成分的特定变化是重要的危险因素，例如高于正常的钙排泄量。然而，导致这些尿液变化的遗传因素尚未明确。因此，在这笔赠款中，我们确定特定的遗传位点或候选基因是否与经过充分研究的人群（奥姆斯特德县热那亚队列）中的肾结石危险因素相关，该人群已经获得了大量的遗传数据。