Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy

Preitner, Frédéric; Bonny, Olivier; Laverrière, Alexandra; Rotman, Samuel; Firsov, Dmitri; Costa, Anabela Da; Metref, Salima; Thorens, Bernard

doi:10.1073/pnas.0904411106

Cited by 218 publications

(185 citation statements)

References 28 publications

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“…Our results are in accord with several recent studies in which SUA was predictive of incident CKD, defined by decrements in eGFR. 50,51 In our study, we found that SLC2A9 SNPs in individual centers were not associated with renal phenotypes. This may be due to genetic heterogeneity between the study centers which stems from the fact that the three study centers are recruited from local tribal communities that are geographically separate and which do not overlap between centers.…”

Section: Discussionmentioning

confidence: 45%

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

et al. 2013

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Increased serum uric acid (SUA) or hyperuricemia, a risk factor for gout, renal and cardiovascular diseases, is caused by either increased production or decreased excretion of uric acid or a mix of both. The solute carrier protein 2 family, member 9 (SLC2A9) gene encodes a transporter that mediates urate flux across the renal proximal tubule. Genome-wide association studies have consistently shown the association of single-nucleotide polymorphisms in this gene with SUA in majority populations. American Indian participants of the Strong Heart Family Study, belonging to multigenerational families, have high prevalence of hyperuricemia. We conducted measured genotype analyses, based on variance components decomposition method and accounting for family relationships, to assess whether the association between SUA and SLC2A9 gene polymorphisms generalized to American Indians (n ¼ 3604) of this study. Seven polymorphisms were selected for genotyping based on their association with SUA levels in other populations. A strong association was found between SLC2A9 gene polymorphisms and SUA in all centers combined (P-values: 1.3 Â 10 À31 -5.1 Â 10 À23 ) and also when stratified by recruitment center; P-values: 1.2 Â 10 À14 -1.0 Â 10 À5 . These polymorphisms were also associated with the estimated glomerular filtration rate and serum creatinine but not albumin-creatinine ratio. In summary, the association of polymorphisms in the uric acid transporter gene with SUA levels extends to a new population of American Indians.

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Section: Discussionmentioning

confidence: 45%

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

et al. 2013

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“…In humans, GLUT9b expression is restricted to the liver and kidney, whereas GLUT9a has a broad tissue distribution including the liver, kidney, intestine, leukocytes, and chondrocytes. This transporter is required for hepatic uric acid uptake, and elective inactivation of the gene coding for the same transporter in mice liver induces severe hyperuricemia (30). In the kidney, GLUT9 has a major influence on uric acid reabsorption (15).…”

Section: Discussionmentioning

confidence: 99%

Association of a Polymorphism in a Gene Encoding a Urate Transporter with CKD Progression

Testa

Mallamaci

Spoto

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Hyperuricemia predicts a high risk for CKD progression but there is no large clinical trial in humans indicating that this relationship is causal in nature. The rs734553 single-nucleotide polymorphism (SNP) of the GLUT9 urate transporter gene was strongly associated with uric acid (UA) levels in a large metaanalysis.Design, setting, participants, & measurements This prospective study adopted the Mendelian randomization approach. The rs734553 SNP was used as an instrumental variable to investigate the relationship between UA and renal outcomes in a cohort of 755 patients with CKD who were enrolled between October 18, 2005, and October 2, 2008. The association between the polymorphism and UA was preliminary confirmed in a series of 211 healthy volunteers enrolled between January 1, 2001, and July 12, 2011, from the same geographic area as the patients with CKD. The study end point was a composite renal-end point (i.e., .30% decrease in the GFR, dialysis, or transplantation). Patients were followed up for a median of 36 months.Results In healthy individuals, serum UA levels were highest in homozygotes for the T allele (risk allele), intermediate in heterozygotes for the same allele, and lowest in those without the risk allele (P,0.001), but no such relationship was found in patients with CKD. In the CKD cohort, homozygotes (TT) and heterozygotes (GT) for the risk allele had a 2.35 times higher risk (hazard ratio, 2.35; 95% confidence interval, 1.25 to 4.42; P=0.008) of CKD progression. The risk for CKD progression by rs734553 remained unmodified in analyses adjusting for proteinuria, GFR, and other classical and CKD-peculiar risk factors.Conclusions A GLUT9 polymorphism, which is strongly associated with serum UA levels in healthy individuals of the general population with normal renal function, holds a strong predictive power for CKD progression. These findings are compatible with the hypothesis that the link between UA and CKD progression is causal in nature.

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“…In polarized epithelial cells, human GLUT9a is expressed in the basolateral membrane, whereas GLUT9b is targeted to the apical pole (84), and in human kidney, GLUT9 is present in the proximal tubule (84). In the mouse, Glut9 is present in the distal convoluted tubule (83), both in the basolateral and apical membranes (87) (Figure 3), but it is not yet known which isoform is present in each pole of the cells, in particular since both mouse isoforms have been reported to be targeted to the basolateral membrane of MDCK cells (83).…”

Section: Other Genes Identified By Genetic Association Studiesmentioning

confidence: 99%

Uric acid transport and disease

Thorens²

2010

J. Clin. Invest.

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Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.Conflict of interest: Alexander So has acted as a consultant and advisor for Novartis.Citation for this article:

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Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy

Cited by 218 publications

References 28 publications

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

Association of a Polymorphism in a Gene Encoding a Urate Transporter with CKD Progression

Uric acid transport and disease

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