The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts

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Abstract
High serum uric acid levels elevate pro-inflammatory–state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 × 10−16), along with eight others (p = 7.75 × 10−16 to 6.05 × 10−11). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values. High serum uric acid levels lead to gout and increase the risk of cardiovascular and kidney disease. To determine what genetic factors might contribute to uric acid levels, we conducted genome-wide scans of single nucleotide variations in DNA in population samples from Sardinia and Chianti. We report here that variants in the GLUT9 gene are associated with altered uric acid levels in both populations. Unexpectedly, rather than being directly involved in uric acid synthesis or secretion, the GLUT9 gene encodes a glucose transporter. It is of interest that the gene is predominantly expressed in liver, a major site of uric acid synthesis, and in kidney, where uric acid is excreted and reabsorbed. However, it now remains to be determined how altered glucose uptake can indirectly affect synthesis or excretion/reabsorption of uric acid, and whether GLUT9 may provide a target for the therapeutic modification of uric acid levels.