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).
Increased serum uric acid or hyperuricemia is a risk factor for kidney and heart disease and gout. The uric acid transporter SLC2A9 regulates uric acid concentrations in blood by regulating uric acid reabsorption and secretion in kidneys. Alteration in the transporter activity can result in hyperuricemia thus increasing the risk for kidney disease gout and heart disease. Thus evaluating the complete variation in the SLC2A9 gene will help us gain better understanding of the mechanism in Mexican Americans as well as American Indians. In addition, this study may provide novel targets for treating these painful diseases and ameliorate their complications.
|Sabo, Aniko; Mishra, Pamela; Dugan-Perez, Shannon et al. (2017) Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children. Obesity (Silver Spring) 25:1270-1276|
|Chittoor, Geetha; Haack, Karin; Mehta, Nitesh R et al. (2017) Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study. BMC Med Genet 18:6|
|Chittoor, Geetha; Kent Jr, Jack W; Almeida, Marcio et al. (2016) GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC Genomics 17:276|
|Butte, Nancy F; Liu, Yan; Zakeri, Issa F et al. (2015) Global metabolomic profiling targeting childhood obesity in the Hispanic population. Am J Clin Nutr 102:256-67|
|Laston, Sandra L; Voruganti, V Saroja; Haack, Karin et al. (2015) Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project. Front Genet 6:6|
|Voruganti, V Saroja; Laston, Sandra; Haack, Karin et al. (2015) Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study. Am J Clin Nutr 101:725-32|
|Voruganti, V Saroja; Franceschini, Nora; Haack, Karin et al. (2014) Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians. Eur J Hum Genet 22:938-43|
|Zhang, Lili; Spencer, Kylee L; Voruganti, V Saroja et al. (2013) Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. Am J Epidemiol 177:923-32|
|Voruganti, Venkata Saroja; Kent Jr, Jack W; Debnath, Subrata et al. (2013) Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans. Front Genet 4:279|