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Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.

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posted on 2012-10-24, 09:04 authored by M. Kolz, T. Johnson, S. Sanna, A. Teumer, V. Vitart, M. Perola, M. Mangino, E. Albrecht, C. Wallace, M. Farrall, A. Johansson, D. R. Nyholt, Y. Aulchenko, J. S. Beckmann, S. Bergmann, M. Bochud, M. Brown, H. Campbell, Consortium EUROSPAN, J. Connell, A. Dominiczak, G. Homuth, C. Lamina, M. I. McCarthy, Consortium ENGAGE, T. Meitinger, V. Mooser, P. Munroe, M. Nauck, J. Peden, H. Prokisch, P. Salo, V. Salomaa, Nilesh J. Samani, D. Schlessinger, M. Uda, U. Völker, G. Waeber, D. Waterworth, R. Wang-Sattler, A. F. Wright, J. Adamski, J. B. Whitfield, U. Gyllensten, J. F. Wilson, I. Rudan, P. Pramstaller, H. Watkins, Consortium PROCARDIS, A. Doering, H. E. Wichmann, Study KORA, T. D. Spector, L. Peltonen, H. Völzke, R. Nagaraja, P. Vollenweider, M. Caulfield, WTCCC, T. Illig, C. Gieger
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.


Major funding for the work described in this manuscript comes from the Medical Research Council of Great Britain (G9521010D), the British Heart Foundation (PG02/128, FS/05/061/19501), the Wellcome Trust (076113/B/04/Z), The Barts and The London Charity, GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1), the Giorgi-Cavaglieri Foundation, the European Framework Project 6 (EuroDia, AnEuploidy and Hypergenes projects), the EUROSPAN (European Special Populations Research Network) project funded by the European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947), the Medical Research Council UK, the Ministry of Science, Education and Sport of the Republic of Croatia (108-1080315-0302, 196-1962766-2751, 196-1962766-2763, 196-1962766-2747), the Helmholtz Zentrum München, the German Federal Ministry of Education and Research, the German National Genome Research Network (NGFN), LMUinnovativ, the Ministry of Health of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, The Swedish Natural Sciences Research Council, The Foundation for Strategic Research, the Scottish Executive Health Department, the Royal Society, the EC Sixth Framework Programme (LSHM-CT-2007-037273), AstraZeneca AB, the Knut and Alice Wallenberg Foundation, the National Institute on Aging (NO1-AG-1-2109 to the “SardiNIA-ProgeNIA” team), the Intramural research funding at the National Institute on Aging (NIH), the Ministry of Cultural Affairs (Germany), the Social Ministry of the Federal State of Mecklenburg-Western Pomerania, Siemens Healthcare, the Federal State of Mecklenburg- West Pomerania, the Australian National Health and Medical Research Council (NHMRC), the US National Institutes of Health (AA007535), the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), the Arthritis Research Campaign, the Chronic Disease Research Foundation, the National Institut



PLoS Genetics, 2009, 5 (6), pp. e1000504-e1000504

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