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）影响高达10%的人口，产生显著的疼痛和痛苦，以及巨大的经济成本（在美国每年高达53亿美元）。治疗策略并不完善，在过去的30年里没有实质性的改进，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确定NL的遗传风险因素。我们的应用程序的一个关键和独特的资源是罗切斯特，MN队列动脉病变遗传流行病学网络（GENOA），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器官并发症（HTN）的基因。特征明确的GENOA队列成员将通过24小时尿产石因素测量（包括钙、草酸、柠檬酸和尿酸排泄）以及总体结晶抑制（亚稳性上限，ULM）对肾结石风险进行表型分析。GENOA队列的大量预先存在的基因分型数据将通过全基因组连锁分析，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lysine的细胞内蛋白酶WNK4、氯通道CLCN5、钙敏感受体、尿凝血酶原片段1、尿酸阴离子转运蛋白1、草酸-甲酸交换剂Slc26a6、tam - 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结石因素相关（例如，24小时钙、草酸、柠檬酸或尿酸排泄；ULM）。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。这将是首次在以人群为基础的队列中评估除钙以外尿结石因素的遗传决定因素的研究，并考虑到饮食这一重要协变量。目标1：在控制饮食因素的情况下，使用方差成分方法进行单变量和多变量定量性状连锁分析，以确定尿结石测量（24小时钙、草酸、柠檬酸和尿酸的排泄；结晶抑制）是否与GENOA队列中的特定基因组区域相关联；目的2：使用基于家族的关联方法来确定尿结石测量（24小时钙、草酸、柠檬酸和尿酸的排泄；结晶抑制）是否与GENOA队列中选定候选基因的多态性相关，调整饮食因素，并确定基因-环境和基因-基因相互作用是否存在。我们的目标是在以社区为基础的队列中建立与尿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费用的一小部分完成。研究结果将为NL的发病机制提供新的认识，并可能导致发现新的潜在治疗靶点。肾结石很常见，已知尿液成分的特定变化是重要的危险因素，例如钙排泄量高于正常水平。然而，导致这些尿液变化的遗传因素尚未得到很好的定义。因此，在这项拨款中，我们确定特定的遗传位点或候选基因是否与肾结石危险因素有关，这些基因位点或候选基因是在一个已经得到大量遗传数据的研究人群中进行的，即奥姆斯特德县热那亚队列。