Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Nature Genetics volume 40, pages 437–442 (2008)Cite this article

Abstract

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200–500 μM) compared with other mammals (3–120 μM)1. About 70% of daily urate disposal occurs via the kidneys, and in 5–25% of the human population, impaired renal excretion leads to hyperuricemia2. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7–5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter3, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association of SLC2A9 SNPs with SUA (−log10 P values) following a genome-wide association scan of 794 Croatians using 308,140 SNPs.
Figure 2: SLC2A9 shows saturable [8-14C]uric acid transport activity in Xenopus laevis oocytes.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Johnson, R.J., Titte, S., Cade, J.R., Rideout, B.A. & Oliver, W.J. Uric acid, evolution and primitive cultures. Semin. Nephrol. 25, 3–8 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Becker, M.A. & Jolly, M. Hyperuricemia and associated diseases. Rheum. Dis. Clin. North Am. 32, 275–293 (2006).

    Article  PubMed  Google Scholar 

  3. Manolescu, A.R., Augustin, R., Moley, K. & Cheeseman, C. A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity. Mol. Membr. Biol. 24, 455–463 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Campbell, H. et al. Effects of genome-wide heterozygosity on a range of biomedically relevant human quantitative traits. Hum. Mol. Genet. 16, 233–241 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Aulchenko, Y.S., de Koning, D.J. & Haley, C. Genomewide rapid association using mixed model and regression: a fast and simple method for genomewide pedigree-based quantitative trait loci association analysis. Genetics 177, 577–585 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Graessler, J. et al. Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population. Arthritis Rheum. 54, 292–300 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Grundy, S.M., Brewer, H.B. Jr., Cleeman, J.I., Smith, S.C. Jr. & Lenfant, C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109, 433–438 (2004).

    Article  PubMed  Google Scholar 

  8. Choi, H.K. & Ford, E.S. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am. J. Med. 120, 442–447 (2007).

    Article  PubMed  Google Scholar 

  9. Ford, E.S., Li, C., Cook, S. & Choi, H.K. Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation 115, 2526–2532 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Seatter, M.J., De la Rue, S.A., Porter, L.M. & Gould, G.W. QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position of D-glucose and is involved in substrate selection at the exofacial binding site. Biochemistry 37, 1322–1326 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Uldry, M. & Thorens, B. The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 447, 480–489 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Phay, J.E., Hussain, H.B. & Moley, J.F. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 66, 217–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Augustin, R. et al. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J. Biol. Chem. 279, 16229–16236 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Keembiyehetty, C. et al. Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes. Mol. Endocrinol. 20, 686–697 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Richardson, S. et al. Molecular characterization and partial cDNA cloning of facilitative glucose transporters expressed in human articular chondrocytes; stimulation of 2-deoxyglucose uptake by IGF-I and elevated MMP-2 secretion by glucose deprivation. Osteoarthritis Cartilage 11, 92–101 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Enomoto, A. & Endou, H. Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease. Clin. Exp. Nephrol. 9, 195–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Hagos, Y., Stein, D., Ugele, B., Burckhardt, G. & Bahn, A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J. Am. Soc. Nephrol. 18, 430–439 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Mount, D.B., Kwon, C.Y. & Zandi-Nejad, K. Renal urate transport. Rheum. Dis. Clin. North Am. 32, 313–331 (2006).

    Article  PubMed  Google Scholar 

  19. Heinig, M. & Johnson, R.J. Role of uric acid in hypertension, renal disease, and metabolic syndrome. Cleve. Clin. J. Med. 73, 1059–1064 (2006).

    Article  PubMed  Google Scholar 

  20. Emmerson, B.T. Effect of oral fructose on urate production. Ann. Rheum. Dis. 33, 276–280 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rutledge, A.C. & Adeli, K. Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr. Rev. 65, S13–S23 (2007).

    Article  PubMed  Google Scholar 

  22. Li, S. et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 3, e194 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wallace, C. et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82, 139–149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rudan, I. et al. Effects of inbreeding, endogamy, genetic admixture, and outbreeding on human health: a (1001 Dalmatians) study. Croat. Med. J. 47, 601–610 (2006).

    PubMed  PubMed Central  Google Scholar 

  25. Kimber, C.H. et al. TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels. Diabetologia 50, 1186–1191 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Morris, A.D. et al. Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. The DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit. Lancet 350, 1505–1510 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Wallace, S.L. et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 20, 895–900 (1977).

    Article  CAS  PubMed  Google Scholar 

  28. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gray, N.K., Coller, J.M., Dickson, K.S. & Wickens, M. Multiple portions of poly(A)-binding protein stimulate translation in vivo. EMBO J. 19, 4723–4733 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was funded by grants from the Medical Research Council (UK), the Wellcome Trust, Arthritis Research Campaign (S.H.R.), and Cancer Research UK (A.T.), an MRC Senior Non-Clinical Fellowship (N.K.G.), and Republic of Croatia Ministry of Science, Education and Sports grants to I.R. (108-1080315-0302), P.R. (196-1962766-2751), B.J. (196-1962766-2763) and N.S.-N. (196-1962766-2747). The Croatian and Scottish (Orcadian) groups are now components of the EU Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) (I.R., H.C., J.F.W., A.F.W., N.D.H.). We thank G.W. Gould, C.I. Cheeseman and I. White for helpful discussions and advice. We acknowledge the Wellcome Trust Clinical Research Facility (Edinburgh) for performing DNA extractions (Orkney) and the genome-wide association scan, J. Ireland for computing support and C. Nicol for the figures. Special thanks to K. Wilson and R. Bisset for administrative support.

Author information

Author notes

  1. Veronique Vitart, Igor Rudan and Caroline Hayward: These authors contributed equally to this work.

Authors and Affiliations

  1. MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK

    Veronique Vitart, Caroline Hayward, Nicola K Gray, Xinhua Shu, Barbara Gorgoni, Joanne Morgan, Susan Campbell, William A Richardson, Peter Hohenstein, Nicholas D Hastie & Alan F Wright

  2. Community Health Sciences, University of Edinburgh, Medical School, Edinburgh, EH8 9AG, UK

    Igor Rudan, Ozren Polasek, James F Wilson, Sarah H Wild, Paul M McKeigue & Harry Campbell

  3. Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, 21000, Croatia

    Igor Rudan

  4. Institute of Evolutionary Biology, University of Edinburgh, King's Buildings, Edinburgh, EH9 3JT, UK

    James Floyd & Sara A Knott

  5. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

    Colin NA Palmer, Charley H Kimber & Louise A Donnelly

  6. Andrija Stampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, 10000, Croatia

    Ivana Kolcic, Ozren Polasek, Zrinka Biloglav & Lina Zgaga

  7. Department of Internal Medicine, Divisions of Pathological Biochemistry and Rheumatology, Carl Gustav Carus Medical School, University of Technology Dresden, Dresden, D-01307, Germany

    Juergen Graessler & Martin Aringer

  8. Department of Chemical Pathology, Purine Research Laboratory, Guy's and St. Thomas' Hospital, King's College, London, SE1 9RT, UK

    Anthony Marinaki

  9. Rheumatic Diseases Unit, Edinburgh, EH4 2XU, UK

    Philip L Riches, Lynette D Fairbanks & Stuart H Ralston

  10. Colon Cancer Genetics Group, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK

    Albert Tenesa

  11. Institute for Anthropological Research, Zagreb, 10000, Croatia

    Branka Janicijevic, Nina Smolej-Narancic, Lovorka Barac-Lauc, Marijana Pericic, Irena Martinovic Klaric, Tatjana Skaric-Juric & Pavao Rudan

  12. School of Clinical Sciences and Community Health, University of Edinburgh, The Chancellor's Building, Edinburgh, EH16 4SB, UK

    Nicola K Gray & Barbara Gorgoni

  13. Division of Medicine and Therapeutics, Diabetes Research Group, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

    Andrew D Morris

Authors
  1. Veronique Vitart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Igor Rudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caroline Hayward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicola K Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James Floyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Colin NA Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sara A Knott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivana Kolcic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ozren Polasek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Juergen Graessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James F Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anthony Marinaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Philip L Riches
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xinhua Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Branka Janicijevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nina Smolej-Narancic
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Barbara Gorgoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Joanne Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Susan Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Zrinka Biloglav
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Lovorka Barac-Lauc
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Marijana Pericic
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Irena Martinovic Klaric
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Lina Zgaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Tatjana Skaric-Juric
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Sarah H Wild
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. William A Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Peter Hohenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Charley H Kimber
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Albert Tenesa
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Louise A Donnelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Lynette D Fairbanks
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Martin Aringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Paul M McKeigue
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Stuart H Ralston
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Andrew D Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Pavao Rudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Nicholas D Hastie
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Harry Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Alan F Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.C., I.R., N.D.H. and A.F.W. designed the study and wrote the paper. V.V., C.H., J.F., S.A.K., A.T. and P.M.M. performed statistical analyses. S.C. and J.M. carried out the genotyping. N.K.G., X.S., B.G., W.A.R. and P.H. made constructs and performed transporter assays. P.R., I.K., O.P., B.J., N.S.-N., Z.B., L.B.-L., M.P., I.M.K., L.Z. and T.S.-J. performed field work and constructed genealogies in Croatia. J.F.W. and S.H.W. provided replication in Orcadian samples. J.G., M.A., P.L.R., S.H.R., A.M. and L.D.F. provided gout and FEUA samples. C.N.A.P., C.H.K., L.A.D. and A.D.M. genotyped and analyzed the Go-DARTS dataset.

Corresponding author

Correspondence to Alan F Wright.

Ethics declarations

Competing interests

We have filed a patent application based on this work.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Tables 1–4 (PDF 90 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vitart, V., Rudan, I., Hayward, C. et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40, 437–442 (2008). https://doi.org/10.1038/ng.106

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.106

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing