Comprehensive SNP discovery in SLC2A9, a candidate gene for uric acid nephropathy

描述（由申请人提供）：血清尿酸（SUA）升高或高尿酸血症是一种与肾脏疾病风险增加相关的代谢问题，并且在全球范围内的患病率正在增加。与其他肾脏疾病的危险因素一样，高尿酸血症也有很强的遗传基础，其遗传模式表明它可能受几个基因的影响。在圣安东尼奥家族心脏研究（SAFHS）最近进行的一项全基因组关联研究中，我们发现墨西哥裔美国人溶质载体家族2、成员9 （SLC2A9）多态性与SUA水平之间存在强烈关联。这是对其他人发表的工作的重复，这些工作表明欧洲高加索人群中SLC2A9基因变异与SUA水平有关。因此，我们建议对SAFHS队列中SLC2A9的变异进行详细和全面的清查，然后在另一组来自圣安东尼奥家族胆囊研究（SAFGS）的墨西哥裔美国人、来自强心脏家族研究（SFHS）的美洲印第安人、来自祖尼印第安人肾脏疾病遗传学（GKDZI）和来自阿拉斯加原住民冠状动脉疾病遗传学（GOCADAN）研究的阿拉斯加爱斯基摩人中使用鉴定的snp进行复制。SLC2A9编码一种转运蛋白，在尿酸稳态中起主要作用，特别是在人类肾脏近曲小管的尿酸分泌和重吸收中。我们在SAFHS的初步数据显示，SLC2A9多态性除了对SUA外，还对肾脏表型的表型变异有显著影响。然而，为了解释SLC2A9基因的所有多态性并捕获由于所有snp引起的最大方差，我们提出了以下具体目标：1)鉴定SLC2A9基因的所有变异，并研究与墨西哥裔美国人SUA和肾脏表型相关的变异；2)对SLC2A9基因（所有外显子、保守内含子和调控区域）进行重测序，发现SFHS美洲印第安人1122名创始人的SNP/多态性，所有参与者的基因型显著SNP；测试与SUA和其他肾脏疾病风险因素的关联，并在另一组GKDZI的美国印第安人和GOCADAN研究的阿拉斯加爱斯基摩人中进行复制；3)验证墨西哥裔美国人、美洲印第安人和阿拉斯加爱斯基摩人中最重要的相关变异的功能。通过应用高通量测序技术和强大的统计和功能方法，我们打算详细了解SLC2A9的遗传结构及其与非欧洲人群中SUA和肾脏疾病风险的关系，包括在两个人群（墨西哥裔美国人和美洲印第安人）中的重测序、复制和确认，以及推广到一个独特的人群（阿拉斯加爱斯基摩人）。

DESCRIPTION (provided by applicant): Increased serum uric acid (SUA) or hyperuricemia is a metabolic problem that is associated with increased renal disease risk and has been increasing in prevalence worldwide. As with other renal disease risk factors, hyperuricemia also has a strong genetic basis, and its pattern of inheritance suggests that it may be influenced by several genes. In a recently conducted genome-wide association study in the San Antonio Family Heart Study (SAFHS), we found a strong association between polymorphisms in solute carrier family 2, member 9 (SLC2A9) and SUA levels in Mexican Americans. This is a replication of published work by others that has shown association of variants in the SLC2A9 gene with SUA levels in European Caucasian populations. Therefore, we propose to conduct a detailed and comprehensive inventory of variation in SLC2A9 in the SAFHS cohort and then to use the identified SNPs for replication efforts in another group of Mexican Americans from the San Antonio Family Gall Bladder study (SAFGS), American Indians of the Strong Heart Family Study (SFHS) and from the Genetics of Kidney Disease in Zuni Indians (GKDZI) and Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. SLC2A9 encodes a transporter that plays a major role in urate homeostasis, specifically in urate secretion and reabsorption in proximal convoluted tubule of kidneys in humans and our preliminary data in SAFHS shows that SLC2A9 polymorphisms have significant influence on the phenotypic variation observed in renal phenotypes in addition to SUA. However in order to account for all polymorphisms in the SLC2A9 gene and capture the maximum variance due to all SNPs we propose the following specific aims: 1) to identify all variation in the SLC2A9 gene and investigate which are associated with SUA and renal phenotypes in Mexican Americans 2) to resequence SLC2A9 gene (all exons, conserved introns and regulatory regions) for SNP/polymorphism discovery in 1122 founders in American Indians of the SFHS, genotype significant SNPs in all participants, test for association with SUA and other renal disease risk factors and pursue replication in another group of American Indians of the GKDZI and Alaskan Eskimos of the GOCADAN study; 3) to validate the functionality of most significantly associated variants in Mexican Americans, American Indians and Alaskan Eskimos. With the application of high-throughput sequencing technology and powerful statistical and functional methodologies, we intend to achieve a detailed understanding of the genetic architecture of SLC2A9 and its association with SUA and renal disease risk in non-European populations, including resequencing and replication and confirmation in two populations (Mexican Americans and American Indians) and generalization to a distinct population (Alaskan Eskimos).