Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

被引：492

作者：

Kolz, Melanie ^{[1
]}

Johnson, Toby ^{[2
,3
,4
]}

Sanna, Serena ^{[5
]}

Teumer, Alexander ^{[6
]}

Vitart, Veronique ^{[7
]}

Perola, Markus ^{[8
,9
]}

Mangino, Massimo ^{[10
]}

Albrecht, Eva ^{[1
]}

Wallace, Chris ^{[11
]}

Farrall, Martin ^{[12
]}

Johansson, Asa ^{[13
,14
]}

Nyholt, Dale R. ^{[15
]}

Aulchenko, Yurii ^{[16
]}

Beckmann, Jacques S. ^{[2
,17
]}

Bergmann, Sven ^{[2
,3
]}

Bochud, Murielle ^{[4
]}

Brown, Morris ^{[18
]}

Campbell, Harry ^{[19
]}

Connell, John ^{[20
]}

Dominiczak, Anna ^{[20
]}

Homuth, Georg ^{[6
]}

Lamina, Claudia ^{[1
,21
]}

McCarthy, Mark I. ^{[13
,22
,23
]}

Meitinger, Thomas ^{[24
]}

Mooser, Vincent ^{[25
]}

Munroe, Patricia ^{[26
]}

Nauck, Matthias ^{[27
,28
]}

Peden, John ^{[12
,13
]}

Prokisch, Holger ^{[24
]}

Salo, Perttu ^{[8
,9
]}

Salomaa, Veikko ^{[8
]}

Samani, Nilesh J. ^{[29
]}

Schlessinger, David ^{[30
]}

Uda, Manuela ^{[5
]}

Voelker, Uwe ^{[6
]}

Waeber, Gerard ^{[31
]}

Waterworth, Dawn ^{[25
]}

Wang-Sattler, Rui ^{[1
]}

Wright, Alan F. ^{[7
]}

Adamski, Jerzy ^{[32
]}

Whitfield, John B. ^{[15
]}

Gyllensten, Ulf ^{[14
]}

Wilson, James F. ^{[19
]}

Rudan, Igor ^{[19
,33
,34
]}

Pramstaller, Peter ^{[31
,35
,36
]}

Watkins, Hugh ^{[12
,13
]}

Doering, Angela ^{[1
]}

Wichmann, H. -Erich ^{[1
,37
]}

Spector, Tim D. ^{[10
]}

Peltonen, Leena ^{[9
,38
]}

机构：

[1] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[2] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland

[3] Swiss Inst Bioinformat, Lausanne, Switzerland

[4] CHU Vaudois, Univ Inst Social & Prevent Med, Vaudois, Switzerland

[5] Ist Neurogenet & Neurofarmacol, Cagliari, Italy

[6] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[7] Western Gen Hosp, MRC, Human Genet Unit, IGMM, Edinburgh EH4 2XU, Midlothian, Scotland

[8] Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[9] Inst Mol Med, FIMM, Helsinki, Finland

[10] Kings Coll London, DTR Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[11] Univ Cambridge, Diabet Inflammat Lab, Cambridge Inst Med Res, Cambridge, England

[12] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[13] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[14] Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, Uppsala, Sweden

[15] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia

[16] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[17] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland

[18] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England

[19] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[20] Univ Glasgow, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland

[21] Innsbruck Med Univ, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, Innsbruck, Austria

[22] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[23] Univ Oxford, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England

[24] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[25] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA USA

[26] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[27] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem, Greifswald, Germany

[28] Ernst Moritz Arndt Univ Greifswald, Labs Med, Greifswald, Germany

[29] Univ Leicester, Glenfield Hosp, Leicester, Leics, England

[30] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[31] CHU Vaudois, Dept Med & Internal Med, CH-1011 Lausanne, Switzerland

[32] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Genome Anal Ctr, Inst Expt Genet, Neuherberg, Germany

[33] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split, Croatia

[34] Gen Info, Zagreb, Croatia

[35] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy

[36] Med Univ Lubeck, Affiliated Inst, Dept Neurol, Cent Hosp, Bolzano, Italy

[37] Univ Munich, IBE, Chair Epidemiol, D-80539 Munich, Germany

[38] Wellcome Trust Sanger Inst, Cambridge, England

[39] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany

来源：

PLOS GENETICS | 2009年 / 5卷 / 06期

基金：

美国国家卫生研究院; 英国医学研究理事会; 瑞士国家科学基金会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; URATE-ANION EXCHANGER; TRIGLYCERIDE LEVELS; FASTING GLUCOSE; SERUM URATE; CARNITINE; GOUT; TRANSPORTER; PROTEIN; SLC2A9;

D O I：

10.1371/journal.pgen.1000504

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：10

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