The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts

Li, Siguang; Sanna, Serena; Maschio, Andrea; Busonero, Fabio; Usala, Gianluca; Mulas, Antonella; Lai, Sandra; Dei, Mariano; Orrù, Marco; Albai, Giuseppe; Bandinelli, Stefania; Schlessinger, David; Lakatta, Edward G.; Scuteri, Angelo; Najjar, Samer S.; Guralnik, Jack M.; Naitza, Silvia; Crisponi, Laura; Cao, Antonio; Abecasis, Gonçalo R.; Ferrucci, Luigi; Uda, Manuela; Chen, Weimin; Nagaraja, Ramaiah

doi:10.1371/journal.pgen.0030194

Cited by 274 publications

(217 citation statements)

References 25 publications

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“…Indeed, genome-wide association studies found that the major locus associated with uric acid plasma levels in human cohorts was the SLC2A9 gene, explaining up to 3.5% of serum uric acid level variations (93). This initial study was rapidly followed by several similar reports that replicated, in other cohorts, the observed association of SLC2A9 with uricemia and demonstrated that human GLUT9 is a urate transporter (69,(94)(95)(96)(97).…”

Section: Figurementioning

confidence: 87%

Uric acid transport and disease

Thorens²

2010

J. Clin. Invest.

691

496

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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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Section: Figurementioning

confidence: 87%

Uric acid transport and disease

Thorens²

2010

J. Clin. Invest.

691

496

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“…Brandstatter et al 5 report strong associations with serum urate for rs6855911, rs644921 and rs7442295 in Bruneck study. Associations were reported for rs6855911 and rs7442295 in SardiNIA and InCHIANTI cohorts 6 and Wallace et al 7 reported an association for rs7442295 in the GRAPHIC, BRIGHT and TwinsUK cohorts. In each of these studies, A QTL for serum urate at 4p15 N Cummings et al consistent with our study results, the direction of the effect showed decreased serum urate levels with each copy of the minor allele and P-values for association with urate ranged from 10 À9 to 10 À13 .…”

Section: Discussionmentioning

confidence: 98%

“…Notably, recent genome-wide association studies have identified a strong positional candidate gene, SLC2A9, in this region. [5][6][7] In this study, we aim to characterize the genetic variation contributing to the linkage signal observed at 4p15.3 by single nucleotide polymorphism (SNP) genotyping the positional candidate SLC2A9 in the Mauritius Family Study population. The Mauritius Family Study focuses on large family pedigrees from a subset of the Mauritian population to minimize heterogeneity and environmental effects.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate

et al. 2010

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Elevated serum urate levels lead to gout and are associated with hypertension, metabolic syndrome, type 2 diabetes and cardiovascular diseases. The purpose of this study was to identify evidence for genetic linkage with serum urate and to determine whether variation within positional candidate genes is associated with serum urate levels in a non-European population. Genetic linkage analysis and single nucleotide polymorphism (SNP) genotyping was performed in a large family pedigree cohort from Mauritius. We assessed associations between serum urate levels and 97 SNPs in a positional candidate gene, SLC2A9. A genome-wide scan identified a new region with evidence for linkage for serum urate at 4p15.3. SNP genotyping identified significant association between six SNP variants in SLC2A9 and serum urate levels. Allelic and gender-based effects were noted for several SNPs. Significant correlations were also observed between serum urate levels and individual components of metabolic syndrome. Our study results implicate genetic variation in SLC2A9 in influencing levels of serum urate over a broad range of values in a large Mauritian family cohort. INTRODUCTIONHyperuricemia is associated with, and often precedes, several cardiovascular disease (CVD) risk factors including hypertension, inflammation, dyslipidemia, kidney disease, obesity, insulin resistance and metabolic syndrome. 1 Furthermore, increased serum urate has been shown to be an independent risk factor for CVD in high-risk individuals. 2 Urate (uric acid) is the end product of purine metabolism in humans due to the evolutionary loss of hepatic urate oxidase (uricase) activity. This loss of enzymatic function has led to uniquely high serum urate levels compared with other mammals. 3 In humans, several factors can lead to increased levels of serum urate (hyperuricemia) as a result of elevated generation and decreased excretion. These include high dietary intake of purines, high fructose intake, alcohol consumption, impaired renal excretion of urate and defective purine metabolism due to genetic disorders, such as hypoxanthine guanine phosphoribosyltransferase deficiency. 4 Given the significant health consequences of variation in serum urate, we sought to understand the mechanisms controlling its levels. In this article, we present the results of our genetic linkage analysis that has identified a novel quantitative trait locus influencing serum urate levels at 4p15.3. Notably, recent genome-wide association studies have identified a strong positional candidate gene, SLC2A9, in this region. [5][6][7] In this study, we aim to characterize the genetic variation contributing to the linkage signal observed at 4p15.3 by single nucleotide polymorphism (SNP) genotyping the positional candidate SLC2A9 in the Mauritius Family Study population. The Mauritius Family Study focuses on large family pedigrees from a subset of the

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“…Recent genetic studies revealed a strong link between urate plasma levels and single nucleotide polymorphisms in the SLC2A9 gene encoding Glut9, a member of the glucose transporter family highly expressed in liver and kidney (15,(16)(17)(18). At least two splice variants have been identified differing only in the length of their amino-terminal cytoplasmic domains.…”

mentioning

confidence: 99%

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

Preitner¹,

Bonny²,

Laverrière

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

231

184

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Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.gout ͉ knockout ͉ nephrolithiasis ͉ uric acid

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The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts

Cited by 274 publications

References 25 publications

Uric acid transport and disease

Uric acid transport and disease

Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate

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

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