Genetic determinants of urine lithogenicity

描述(申请人提供)：肾结石(NL)影响多达10%的人口，产生巨大的痛苦和痛苦，以及巨大的经济损失(在美国，每年高达53亿美元)。治疗策略不完善，在过去30年中没有实质性的改善，部分原因是关键的致病步骤仍然定义不清。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。我们应用程序的一个关键和独特的资源是动脉病遗传流行病学网络(Genoa)的MN罗切斯特队列，该队列进行了全基因组链接和关联研究，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小时尿液中钙、草酸盐、柠檬酸盐和尿酸排泄以及总体结晶抑制(亚稳上限，ULM)等致石因素的测量，将对具有良好特征的热那亚队列中的成员进行肾结石风险的表型鉴定。将通过全基因组连接以及选定的NL候选基因关联(维生素D受体、可溶腺苷环化酶、不含赖氨酸的细胞内蛋白水解酶WNK4、氯通道CLCN5、钙感应受体、尿凝血酶原片段1、尿酸阴离子转运体1、草酸-甲酸交换器Slc26a6、Tamm-Horsfall蛋白、骨桥蛋白和Bikunin)来分析热那亚人群中广泛存在的基因分型数据。这些研究将确定特定的基因或候选基因是否与相应的尿路致石因子相关(例如，24小时排出的钙、草酸、柠檬酸或尿酸；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。考虑到饮食这一重要的协变量，这将是第一次在基于人群的队列中评估除钙以外的尿石致石因素的遗传决定因素。具体目标是：目标1：使用单变量和多变量数量性状连锁分析的方差分量方法来确定尿致结石措施(24小时排泄钙、草酸、柠檬酸盐和尿酸；结晶抑制)是否映射到基因组队列中的特定基因组区域，并控制饮食因素；目标2：使用基于家族的关联方法来确定尿致结石措施(24小时排泄钙、草酸、柠檬酸盐和尿酸；结晶抑制)是否与Genoa队列中选定候选基因的多态相关，并对饮食因素进行调整，并确定是否存在基因-环境和基因-基因交互作用。我们的目标是在以社区为基础的队列中建立与尿液NL危险因素的遗传关联。热那亚调查人员的丰富经验和基础设施，以及对先前存在的基因分型数据的使用，将使这些研究能够以原本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见解，并可能导致新的潜在治疗靶点的确定。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还没有得到很好的界定。因此，在这项资助中，我们确定了在奥姆斯特县热那亚队列中已经有大量遗传数据的经过充分研究的人群中，特定的遗传位点或候选基因是否与肾结石风险因素有关。

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.