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SLC2A9 is a high-capacity urate transporter in humans

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Caulfield, Mark, Munroe, Patricia B., O'Neill, Deb, Witkowska, Kate, Charchar, Fadi J., Doblado, Manuel, Evans, Sarah, Eyheramendy, Susana, Onipinla, Abiodun, Howard, Philip et al.
(2008) SLC2A9 is a high-capacity urate transporter in humans. PL o S Medicine, Vol.5 (No.10). doi:10.1371/journal.pmed.0050197 ISSN 1549-1277.

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Official URL: http://dx.doi.org/10.1371/journal.pmed.0050197

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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 SLC2A9 gene
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
lM). 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=27μM). 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: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016)
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Uric acid -- Physiological transport, Glucose -- Physiological transport, Gout -- Genetic aspects
Journal or Publication Title: PL o S Medicine
Publisher: Public Library of Science
ISSN: 1549-1277
Official Date: 7 October 2008
Dates:
DateEvent
7 October 2008Published
Volume: Vol.5
Number: No.10
Number of Pages: 15
DOI: 10.1371/journal.pmed.0050197
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Funder: Economic and Social Research Council (Great Britain) (ESRC), Medical Research Council (Great Britain) (MRC), British Heart Foundation, American Diabetes Association (ADA), National Institutes of Health (U.S.) (NIH), Canadian Breast Cancer Foundation, Wellcome Trust (London, England), Barts and The London NHS Trust, Estonia. Haridus- ja Teadusministeerium [The Ministry of Education and Science], Great Britain. Health and Safety Executive, Great Britain. Dept. of Health (DoH), National Heart, Lung, and Blood Institute, National Institute on Aging (NIA), United States. Agency for Health Care Policy and Research, John D. and Catherine T. MacArthur Foundation
Grant number: G9521010D (MRC), PG02/128 (BHF), NIH-NIDDK T32-DK07120 (NIH), 076113/B/04/Z (Wellcome), FS/05/061/19501 (BHF), 070191/Z/03/Z (Wellcome), 0182721s06 (Estonia), HL36310 (NHLBI), AG13196 (NIA), HS06516 (AHCPR), AG1764406S1 (NIA)

Data sourced from Thomson Reuters' Web of Knowledge

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