Sex-Specific Association of the Putative Fructose TransporterSLC2A9Variants With Uric Acid Levels Is Modified by BMI

Anita Brandstätter; Stefan Kiechl; Barbara Kollerits; Steven C. Hunt; Iris M. Heid; Stefan Coassin; Johann Willeit; Ted D. Adams; Thomas Illig; Paul N. Hopkins; Florian Kronenberg

doi:10.2337/dc08-0349

journal article Aug 01, 2008

Sex-Specific Association of the Putative Fructose TransporterSLC2A9Variants With Uric Acid Levels Is Modified by BMI

Anita Brandstätter Stefan Kiechl

Barbara Kollerits Steven C. Hunt Iris M. Heid Stefan Coassin Johann Willeit

Ted D. Adams Thomas Illig Paul N. Hopkins Florian Kronenberg

Diabetes Care Vol. 31 No. 8 pp. 1662-1667 · American Diabetes Association

View at Publisher Save 10.2337/dc08-0349

Abstract

OBJECTIVE—High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity.RESEARCH DESIGN AND METHODS—Four single nucleotide polymorphisms within SLC2A9 (rs6855911, rs7442295, rs6449213, and rs12510549) were genotyped in the population-based prospective Bruneck Study (n = 800) and in a case-control study from Utah including 1,038 subjects recruited for severe obesity and 831 control subjects.RESULTS—We observed highly significant associations between all four polymorphisms and uric acid levels in all study groups. Each copy of the minor allele decreased age- and sex-adjusted uric acid levels by 0.30–0.35 mg/dl on average, which translates to a relative decrease of 5–6% with P values ranging from 10−9 to 10−11 in the combined analysis. An extended adjustment for BMI, creatinine, gout medication, and alcohol intake improved P values to a range of 10−14 to 10−20. The association was more pronounced in women and the population-based Bruneck Study and was significantly modified by BMI, with stronger effect sizes in individuals with high BMI.CONCLUSIONS—Genetic variants within SLC2A9 have significant effects on uric acid levels and are modified by sex and BMI.

Topics

No keywords indexed for this article. Browse by subject →

References

24

[1]

Ames BN, Cathcart R, Schwiers E, et al.: Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 78: 6858–6862, 1981 10.1073/pnas.78.11.6858

[2]

Kanellis J, Kang DH: Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol 25:39–42, 2005 10.1016/j.semnephrol.2004.09.007

[3]

Serum Concentrations of Uric Acid and the Metabolic Syndrome Among US Children and Adolescents

Earl S. Ford, Chaoyang Li, Stephen Cook et al.

Circulation 10.1161/circulationaha.106.657627

[4]

Facchini F, Chen YD, Hollenbeck CB, et al.: Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 266:3008–3011, 1991 10.1001/jama.266.21.3008

[5]

Dehghan A, van Hoek M, Sijbrands EJ, et al.: High serum uric acid as a novel risk factor for type 2 diabetes mellitus. Diabetes Care2007 10.2337/dc07-1276

[6]

Wilk JB, Djousse L, Borecki I, et al.: Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum Genet 106:355–359, 2000 10.1007/s004390000243

[7]

Yang Q, Guo CY, Cupples LA, et al.: Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 54:1435–1441, 2005 10.1016/j.metabol.2005.05.007

[8]

Li S, Sanna S, Maschio A, et al.: The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 3:e194, 2007 10.1371/journal.pgen.0030194

[9]

Wallace C, Newhouse SJ, Braund P, 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 10.1016/j.ajhg.2007.11.001

[10]

Döring A, Gieger C, Mehta D, et al.: SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 40:430–436, 2008 10.1038/ng.107

[11]

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 10.1038/ng.106

[12]

Miller A, Adeli K: Dietary fructose and the metabolic syndrome. Curr Opin Gastroenterol 24:204–209, 2008 10.1097/mog.0b013e3282f3f4c4

[13]

Kiechl S, Willeit J, Mayr M, et al.: Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity and 10-year cardiovascular outcomes: prospective results from the Bruneck Study. Arterioscler Thromb Vasc Biol 27:1788–1795, 2007 10.1161/atvbaha.107.145805

[14]

Schoenborn V, Heid IM, Vollmert C, et al.: The ATGL gene is associated with free fatty acids, triglycerides and type 2 diabetes. Diabetes 55:1270–1275, 2006 10.2337/db05-1498

[15]

Diagnosis and Management of the Metabolic Syndrome

Scott M. Grundy, James I. Cleeman, Stephen R. Daniels et al.

Circulation 10.1161/circulationaha.105.169404

[16]

Horsley V, Pavlath GK: NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol 156:771–774, 2002 10.1083/jcb.200111073

[17]

Joost HG, Thorens B: The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol 18:247–256, 2001 10.1080/09687680110090456

[18]

Stirpe F, Della CE, Bonetti E, et al.: Fructose-induced hyperuricaemia. Lancet 2:1310–1311, 1970 10.1016/s0140-6736(70)92269-5

[19]

Choi HK, Curhan G: Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 336:309–312, 2008 10.1136/bmj.39449.819271.be

[20]

Hallfrisch J: Metabolic effects of dietary fructose. FASEB J 4:2652–2660, 1990 10.1096/fasebj.4.9.2189777

[21]

Johnson RJ, Segal MS, Sautin Y, et al.: Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 86:899–906, 2007 10.1093/ajcn/86.4.899

[22]

Bray GA, Nielsen SJ, Popkin BM: Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79:537–543, 2004 10.1093/ajcn/79.4.537

[23]

Nakagawa T, Hu H, Zharikov S, et al.: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:F625–F631, 2006 10.1152/ajprenal.00140.2005

[24]

Patsopoulos NA, Tatsioni A, Ioannidis JP: Claims of sex differences: an empirical assessment in genetic associations. JAMA 298:880–893, 2007 10.1001/jama.298.8.880

Metrics

78

Citations

24

References

Details

Published: Aug 01, 2008
Vol/Issue: 31(8)
Pages: 1662-1667

Authors

A

Anita Brandstätter

Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

S

Stefan Kiechl

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

B

Barbara Kollerits

Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

S

Steven C. Hunt

Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah

I

Iris M. Heid

Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Information Management, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Munich, Germany

S

Stefan Coassin

Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

J

Johann Willeit

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

T

Ted D. Adams

Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah

T

Thomas Illig

Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

P

Paul N. Hopkins

Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah

F

Florian Kronenberg

Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

Cite This Article

Anita Brandstätter, Stefan Kiechl, Barbara Kollerits, et al. (2008). Sex-Specific Association of the Putative Fructose TransporterSLC2A9Variants With Uric Acid Levels Is Modified by BMI. Diabetes Care, 31(8), 1662-1667. https://doi.org/10.2337/dc08-0349

Sex-Specific Association of the Putative Fructose TransporterSLC2A9Variants With Uric Acid Levels Is Modified by BMI

You May Also Like