Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish
Article first published online: 29 AUG 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 58, Issue 9, pages 2874–2881, September 2008
How to Cite
McArdle, P. F., Parsa, A., Chang, Y.-P. C., Weir, M. R., O'Connell, J. R., Mitchell, B. D. and Shuldiner, A. R. (2008), Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish. Arthritis & Rheumatism, 58: 2874–2881. doi: 10.1002/art.23752
- Issue published online: 29 AUG 2008
- Article first published online: 29 AUG 2008
- Manuscript Accepted: 12 MAY 2008
- Manuscript Received: 29 FEB 2008
- NIH. Grant Numbers: U01-HL-72515, U01-HL-084756
- National Center for Research Resources [NCRR]. Grant Number: M01-RR-16500
- University of Maryland General Clinical Research Center
- NCRR. Grant Number: M01-RR-000052
- Johns Hopkins University General Clinical Research Center
- NCRR. Grant Number: P30-DK-072488
- Clinical Nutrition Research Unit of Maryland
- USDA Cooperative State Research, Education, and Extension Service Animal Genome Program (National Research Initiative. Grant Number: 2007-35205-17883
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).
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.
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).
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.