Genetic determinants of urine lithogenicity

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）。治疗策略是不完善的，在过去的30年里没有得到实质性的改善，部分原因是关键的致病步骤仍然没有得到很好的定义。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。我们申请的一个关键和独特的资源是罗切斯特，MN队列的遗传流行病学网络动脉病（GENOA），进行了全基因组的连锁和关联研究，以确定影响血压和高血压（HTN）的终末器官并发症的基因。将通过24小时尿致石因子（包括钙、草酸盐、柠檬酸盐和尿酸排泄）以及总体结晶抑制（亚稳性上限，乌尔姆）测量，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以及选定的NL候选基因关联，分析GENOA队列的大量既存基因分型数据（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WNK 4、氯离子通道CLCN 5、钙敏感受体、尿凝血酶原片段1、尿酸盐阴离子转运蛋白1、尿酸盐-甲酸盐交换体Slc 26 a6、Tamm-Horsfall蛋白、骨桥蛋白、和bikunin）。这些研究将确定特定的基因座或候选基因是否与相应的尿结石形成因素相关（例如，钙、草酸盐、柠檬酸盐或尿酸的24小时排泄;乌尔姆）。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。这将是第一个研究，以评估遗传因素的尿结石因素以外的钙在人口为基础的队列，考虑到饮食的重要协变量。具体目标是：目标一：使用方差分量法进行单变量和多变量数量性状连锁分析，以确定尿结石指标是否（钙、草酸盐、柠檬酸盐和尿酸的24小时排泄;结晶抑制）映射到GENOA队列中的特定基因组区域，控制饮食因素;目标#2：使用以家庭为基础的关联方法，以确定是否尿结石的措施（24小时钙、草酸、柠檬酸和尿酸排泄;结晶抑制）与GENOA组群中所选候选基因的多态性相关，调整饮食因素，并确定是否存在基因-环境和基因-基因相互作用。我们的目标是在一个以社区为基础的队列中建立与尿NL危险因素的遗传关联。GENOA研究者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得以完成，而所需费用仅为所需费用的一小部分。这些结果将为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。肾结石是常见的，并且已知尿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。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，在这项研究中，我们确定了特定的遗传位点或候选基因是否与奥姆斯特德县GENOA队列中大量遗传数据已经存在的经过充分研究的人群中的肾结石风险因素相关。

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.