Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the NIA. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. AG13196) NIH, Agency for Health Care Policy Research (grant no. H元6310) and from the US: NIH, National Institute on Aging (NIA grant no. The Whitehall II study has been supported by grants from the UK: MRC Economic and Social Research Council British Heart Foundation Health and Safety Executive Department of Health National Heart Lung and Blood Institute (grant no. Marmot is supported by an MRC Research Professorship. 070191/Z/03/Z) in Biomedical Science in Central Europe and by Estonian Ministry of Education and Science core grant no. The HYPEST sample collection was financed by Wellcome Trust International Senior Research Fellowship to M. The LOLIPOP Study was funded by the British Heart Foundation. Wallace is funded by the British Heart Foundation (grant no. Samani are British Heart Foundation Chair holders. The Barts and The London Charity funded the Barts and The London Genome Centre. The Wellcome Trust Case Control Consortium was funded by the Wellcome Trust (grant number 076113/B/04/Z). Cheeseman is funded by the Canadian Breast Cancer Foundation. Evans is funded by National Institutes of Health (NIH) grant no. Moley is supported by an American Diabetes Association Research Grant. G9521010D) and the British Heart Foundation (grant no. 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.įunding: The BRIGHT study and current work are supported by the Medical Research Council (MRC) of Great Britain (grant no. Received: FebruAccepted: AugPublished: October 7, 2008Ĭopyright: © 2008 Caulfield et al. PLoS Med 5(10):Īcademic Editor: Andrew Hattersley, Peninsula Medical School, United Kingdom (2008) SLC2A9 Is a High-Capacity Urate Transporter in Humans. 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).Ĭitation: Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M, et al. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval 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 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. 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. 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. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner ( K i = 27 μM). 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. Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. 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).
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