Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations

Kolz, M. et al. (2009) Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genetics, 5(6), e1000504. (doi: 10.1371/journal.pgen.1000504)

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Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10<sup>-201</sup>), ABCG2 (p = 3.1x10<sup>-26</sup>), SLC17A1 (p = 3.0x10<sup>-14</sup>), SLC22A11 (p = 6.7x10<sup>-14</sup>), SLC22A12 (p = 2.0x10<sup>-9</sup>), SLC16A9 (p = 1.1x10<sup>-8</sup>), GCKR (p = 1.4x10<sup>-29</sup>), LRRC16A (p = 8.5x10<sup>-9</sup>), and near PDZK1 (p = 2.7x10<sup>-9</sup>). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10<sup>-26</sup>) and propionyl-L-carnitine (p = 5.0x10<sup>-8</sup>) concentrations, which in turn were associated with serum UA levels (p = 1.4x10<sup>-57</sup> and p = 8.1x10<sup>-54</sup>, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Connell, Professor John and Dominiczak, Professor Anna
Authors: Kolz, M., Johnson, T., Sanna, S., Teumer, A., Vitart, V., Perola, M., Mangino, M., Albrecht, E., Wallace, C., Farrall, M., Johansson, Å., Nyholt, D. R., Aulchenko, Y., Beckmann, J. S., Bergmann, S., Bochud, M., Brown, M., Campbell, H., Connell, J., Dominiczak, A., Homuth, G., Lamina, C., McCarthy, M. I., Meitinger, T., Mooser, V., Munroe, P., Nauck, M., Peden, J., Prokisch, H., Salo, P., Salomaa, V., Samani, N. J., Schlessinger, D., Uda, M., Völker, U., Waeber, G., Waterworth, D., Wang-Sattler, R., Wright, A. F., Adamski, J., Whitfield, J. B., Gyllensten, U., Wilson, J. F., Rudan, I., Pramstaller, P., Watkins, H., Doering, A., Wichmann, H.-E., Spector, T. D., Peltonen, L., Völzke, H., Nagaraja, R., Vollenweider, P., Caulfield, M., Illig, T., and Gieger, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN (Online):1553-7404
Published Online:05 June 2009
Copyright Holders:Copyright © 2009 The Authors
First Published:First published in PLoS Genetics 5(6):e1000504
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874RI CARDIOVASCULAR & MEDICAL SCIENCES