SLC2A9 is a high-capacity urate transporter in humans

Caulfield, M. J. et al. (2008) SLC2A9 is a high-capacity urate transporter in humans. PLoS Medicine, 5(10), e197. (doi: 10.1371/journal.pmed.0050197)

Abstract

Background
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.

Methods and Findings
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82).

Conclusions
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.

• Item Type: Articles
• Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dominiczak, Professor Anna and Connell, Professor John
• Authors: Caulfield, M. J., Munroe, P. B., O'Neill, D., Witkowska, K., Charchar, F. J., Doblado, M., Evans, S., Eyheramendy, S., Onipinla, A., Howard, P., Shaw-Hawkins, S., Dobson, R. J., Wallace, C., Newhouse, S. J., Brown, M., Connell, J. M., Dominiczak, A., Farrall, M., Lathrop, G. M., Samani, N. J., Kumari, M., Marmot, M., Brunner, E., Chambers, J., Elliot, P., Kooner, J., Lann, M., Org, E., Veldre, G., Viigimaa, M., Cappucio, F. P., Ji, C., Iacone, R., Strazullo, P., Moley, K. H., and Cheeseman, C.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: PLoS Medicine
• Publisher: Public Library of Science
• ISSN: 1549-1277
• ISSN (Online): 1549-1676
• Published Online: 01 January 2008
• Copyright Holders: © 2008 Caulfield et al.
• First Published: First published in PLoS Medicine 2008 5(10): e197
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

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Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
39252	1	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences
39252	2	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences