Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish

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Abstract
Objective Uric acid is the primary end product of purine metabolism. Increased serum uric acid levels have been associated with gouty arthritis as well as with a variety of cardiovascular‐related phenotypes. This study was undertaken to investigate associations between uric acid levels and single‐nucleotide polymorphisms (SNPs). Methods A 500,000‐SNP genome‐wide association study of serum uric acid levels was performed in a cohort of Old Order Amish from Lancaster County, Pennsylvania. Results The scan confirmed a previously identified region on chromosome 4 to be strongly associated with uric acid levels (P = 4.2 × 10−11 for rs10489070). Followup genotyping revealed that a nonsynonymous coding SNP (Val253Ile; rs16890979) in GLUT9 was most strongly associated with uric acid levels, with each copy of the minor allele associated with a decrease of 0.47 mg/dl in the uric acid level (95% confidence interval 0.31–0.63 [P = 1.43 × 10−11]). The effect of this variant tended to be stronger in women than in men (P = 0.16 for sex–genotype interaction). The genotype effect was not modified by the inclusion of several cardiovascular risk factors, suggesting that GLUT9 is directly related to uric acid homeostasis. The SNP identified in the genome‐wide scan in the Amish population (rs10489070) was also significantly associated with gout in the Framingham Heart Study (P = 0.004). Conclusion Our findings indicate that GLUT9, which is expressed in the kidney, may be a novel regulator of uric acid elimination and that a common nonsynonymous variant in this gene contributes to abnormalities in uric acid homeostasis and gout.