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

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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).