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

被引：491

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：

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

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

共 45 条

[21] Transethnic meta-analysis of exome-wide variants identifies new loci associated with male-specific metabolic syndrome
Lee, Ho-Sun
Kim, Boram
Park, Taesung
GENES & GENOMICS, 2022, 44 (05) : 629 - 636
[22] Transethnic meta-analysis of exome-wide variants identifies new loci associated with male-specific metabolic syndrome
Ho-Sun Lee
Boram Kim
Taesung Park
Genes & Genomics, 2022, 44 : 629 - 636
[23] Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals
Kilpelaeinen, Tuomas O.
den Hoed, Marcel
Ong, Ken K.
Grontved, Anders
Brage, Soren
Jameson, Karen
Cooper, Cyrus
Khaw, Kay-Tee
Ekelund, Ulf
Wareham, Nicholas J.
Loos, Ruth J. F.
AMERICAN JOURNAL OF CLINICAL NUTRITION, 2011, 93 (04): : 851 - 860
[24] Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor
Wang, Zhaoming
McGlynn, Katherine A.
Rajpert-De Meyts, Ewa
Bishop, D. Timothy
Chung, Charles C.
Dalgaard, Marlene D.
Greene, Mark H.
Gupta, Ramneek
Grotmol, Tom
Haugen, Trine B.
Karlsson, Robert
Litchfield, Kevin
Mitra, Nandita
Nielsen, Kasper
Pyle, Louise C.
Schwartz, Stephen M.
Thorsson, Vesteinn
Vardhanabhuti, Saran
Wiklund, Fredrik
Turnbull, Clare
Chanock, Stephen J.
Kanetsky, Peter A.
Nathanson, Katherine L.
NATURE GENETICS, 2017, 49 (07) : 1141 - +
[25] Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor
Zhaoming Wang
Katherine A McGlynn
Ewa Rajpert-De Meyts
D Timothy Bishop
Charles C Chung
Marlene D Dalgaard
Mark H Greene
Ramneek Gupta
Tom Grotmol
Trine B Haugen
Robert Karlsson
Kevin Litchfield
Nandita Mitra
Kasper Nielsen
Louise C Pyle
Stephen M Schwartz
Vésteinn Thorsson
Saran Vardhanabhuti
Fredrik Wiklund
Clare Turnbull
Stephen J Chanock
Peter A Kanetsky
Katherine L Nathanson
Nature Genetics, 2017, 49 : 1141 - 1147
[26] Genome-Wide Association Meta-Analysis Including 123,000 Individuals Identifies 20 New Obesity Susceptibility Loci
Loos, Ruth J. F.
DIABETES, 2010, 59 : A15 - A15
[27] Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
Pankratz, Nathan
Schick, Ursula M.
Zhou, Yi
Zhou, Wei
Ahluwalia, Tarunveer Singh
Allende, Maria Laura
Auer, Paul L.
Bork-Jensen, Jette
Brody, Jennifer A.
Chen, Ming-Huei
Clavo, Vinna
Eicher, John D.
Grarup, Niels
Hagedorn, Elliott J.
Hu, Bella
Hunker, Kristina
Johnson, Andrew D.
Leusink, Maarten
Lu, Yingchang
Lyytikainen, Leo-Pekka
Manichaikul, Ani
Marioni, Riccardo E.
Nalls, Mike A.
Pazoki, Raha
Smith, Albert Vernon
van Rooij, Frank J. A.
Yang, Min-Lee
Zhang, Xiaoling
Zhang, Yan
Asselbergs, Folkert W.
Boerwinkle, Eric
Borecki, Ingrid B.
Bottinger, Erwin P.
Cushman, Mary
de Bakker, Paul I. W.
Deary, Ian J.
Dong, Liguang
Feitosa, Mary F.
Floyd, James S.
Franceschini, Nora
Franco, Oscar H.
Garcia, Melissa E.
Grove, Megan L.
Gudnason, Vilmundur
Hansen, Torben
Harris, Tamara B.
Hofman, Albert
Jackson, Rebecca D.
Jia, Jia
Kahonen, Mika
NATURE GENETICS, 2016, 48 (08) : 867 - +
[28] Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence
Suzanne Sniekers
Sven Stringer
Kyoko Watanabe
Philip R Jansen
Jonathan R I Coleman
Eva Krapohl
Erdogan Taskesen
Anke R Hammerschlag
Aysu Okbay
Delilah Zabaneh
Najaf Amin
Gerome Breen
David Cesarini
Christopher F Chabris
William G Iacono
M Arfan Ikram
Magnus Johannesson
Philipp Koellinger
James J Lee
Patrik K E Magnusson
Matt McGue
Mike B Miller
William E R Ollier
Antony Payton
Neil Pendleton
Robert Plomin
Cornelius A Rietveld
Henning Tiemeier
Cornelia M van Duijn
Danielle Posthuma
Nature Genetics, 2017, 49 : 1107 - 1112
[29] Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
Nature Genetics, 2016, 48 : 867 - 876
[30] Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus
David L Morris
Yujun Sheng
Yan Zhang
Yong-Fei Wang
Zhengwei Zhu
Philip Tombleson
Lingyan Chen
Deborah S Cunninghame Graham
James Bentham
Amy L Roberts
Ruoyan Chen
Xianbo Zuo
Tingyou Wang
Leilei Wen
Chao Yang
Lu Liu
Lulu Yang
Feng Li
Yuanbo Huang
Xianyong Yin
Sen Yang
Lars Rönnblom
Barbara G Fürnrohr
Reinhard E Voll
Georg Schett
Nathalie Costedoat–Chalumeau
Patrick M Gaffney
Yu Lung Lau
Xuejun Zhang
Wanling Yang
Yong Cui
Timothy J Vyse
Nature Genetics, 2016, 48 : 940 - 946

← 1 2 3 4 5 →