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SLC2A9 influences uric acid concentrations with pronounced sex-specific effects

Abstract

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: −0.23 to −0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 × 10−8 to 1.0 × 10−32. Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.

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Figure 1: Summary of genome-wide association and replication results.
Figure 2: Transcription analysis of SLC2A9 and association with serum uric acid concentrations.

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Acknowledgements

The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The SHIP genotyping was supported by grant 03IP612 (InnoProfile) of the German Federal Ministry for Education and Research (BMBF). Part of the work on SAPHIR was supported by the 'Genomics of Lipid-associated Disorders – GOLD' of the Austrian Genome Research Programme (GEN-AU). We gratefully acknowledge the contribution of P. Lichtner, G. Eckstein, T. Strom and K. Heim and all other members of the Helmholtz Zentrum München genotyping staff in generating and analyzing the SNP and RNA dataset, as well as the contribution of A. Gehringer and M. Haak from the Division of Genetic Epidemiology, Innsbruck Medical University. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies, the SHIP study and the SAPHIR study. Finally, we express our appreciation to all study participants.

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Contributions

Study design and biobanking KORA F3 500K: H.-E.W., T.M., C.G., T.I., C.M., A.P. and G.F.; study design and biobanking replication studies: H.V. (SHIP), B.P. and F.K. (SAPHIR), A.D. and H.-E.W. (KORA); statistical analysis: C.G. and A.D.; Affymetrix genotyping: T.M. and T.I.; genotyping in the replication studies: F.K., S.C., D.R., K.H., N.K. and H.G.; sequencing and gene expression analysis: T.M., D.M., H.P. and A.P.; phenotype assessment: H.V., B.P., A.D., C.M. and H.-E.W.; bioinformatical analysis: S.C., H.G.; manuscript writing: C.M., A.D, C.G., T.M., H.G., S.C. and F.K.

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Correspondence to Christa Meisinger.

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Supplementary Methods, Supplementary Tables 1–7, Supplementary Figure 1 (PDF 547 kb)

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

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