Project Summary Gout, an inflammatory arthritis, is estimated to affect approximately 10 million Americans. Gout and hyperuricemia, the predisposing metabolic abnormality associated with gout, are associated with several co- morbidities, including chronic kidney disease, diabetes, cardiovascular disease and the metabolic syndrome. Genome-wide association studies (GWAS) have identified >40 genes that influence serum urate concentration (sUA); SLC2A9, encoding the electrogenic urate transporter GLUT9 (glucose transporter 9), was identified as having the highest impact. GLUT9 is the exclusive basolateral exit step in uric acid reabsorption, with bi-allelic loss of function mutations of SLC2A9 leading to hypouricemia with a marked activation of renal urate secretion, nephrolithiasis, and exercise-induced acute kidney injury (“renal hypouricemia”). We suspect that GLUT9 may be regulated by the evolutionary conserved AMP-sensitive kinase (AMPK), and more specifically by PRKAG2, which encodes the ϒ2 subunit. PRKAG2 has been extensively studied with regards to its role in the development of a familial hypertrophic cardiomyopathy syndrome; single nucleotide polymorphisms (SNPs) in PRKAG2 identified in GWAS have also been linked to development of chronic kidney disease, hyperuricemia and increased risk of gout. AMPK, an energy sensor involved in the regulation of glucose metabolism and insulin sensitivity, is a known regulator of members of the GLUT family. The sponsor's laboratory has demonstrated that GLUT9 is the dominant insulin- activated re-absorptive urate transporter, providing a mechanistic explanation for the urate-retaining effects of hyperinsulinemia. We will obtain information on rare coding variants of PRKAG2 from whole exome sequencing and re-sequencing data sets and evaluate their differential effects on the urate transport capacity of GLUT9. Given the interconnected nature between AMPK and the development of several metabolic diseases, we have reason to believe that AMPK plays a pivotal role in the regulation of GLUT9-mediated urate transport, such that these studies will impact considerably on our collective understanding of the molecular physiology of urate homeostasis and the pathogenesis of gout.