Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

被引：432

作者：

Chambers, John C. ^{[1
,2
,3
]}

Zhang, Weihua ^{[1
,3
]}

Sehmi, Joban ^{[3
,4
]}

Li, Xinzhong ^{[5
]}

Wass, Mark N. ^{[6
]}

Van der Harst, Pim ^{[7
]}

Holm, Hilma ^{[8
]}

Sanna, Serena ^{[9
]}

Kavousi, Maryam ^{[10
,11
]}

Baumeister, Sebastian E. ^{[12
]}

Coin, Lachlan J. ^{[1
]}

Deng, Guohong ^{[13
]}

Gieger, Christian ^{[14
]}

Heard-Costa, Nancy L. ^{[15
]}

Hottenga, Jouke-Jan ^{[16
]}

Kuehnel, Brigitte ^{[14
]}

Kumar, Vinod ^{[17
]}

Lagou, Vasiliki ^{[18
,19
,20
]}

Liang, Liming ^{[21
,22
]}

Luan, Jian'an ^{[23
]}

Vidal, Pedro Marques ^{[24
,25
]}

Leach, Irene Mateo ^{[7
]}

O'Reilly, Paul F. ^{[1
]}

Peden, John F. ^{[26
]}

Rahmioglu, Nilufer ^{[19
]}

Soininen, Pasi ^{[27
,28
,29
]}

Speliotes, Elizabeth K. ^{[30
,31
]}

Yuan, Xin ^{[32
]}

Thorleifsson, Gudmar ^{[8
]}

Alizadeh, Behrooz Z. ^{[18
]}

Atwood, Larry D. ^{[33
]}

Borecki, Ingrid B. ^{[34
]}

Brown, Morris J. ^{[35
]}

Charoen, Pimphen ^{[1
,36
]}

Cucca, Francesco ^{[9
]}

Das, Debashish ^{[3
]}

de Geus, Eco J. C. ^{[16
,37
,38
]}

Dixon, Anna L. ^{[39
]}

Doering, Angela ^{[40
]}

Ehret, Georg ^{[25
,41
,42
,43
]}

Eyjolfsson, Gudmundur I. ^{[44
]}

Farrall, Martin ^{[26
,45
]}

Forouhi, Nita G. ^{[23
]}

Friedrich, Nele ^{[46
]}

Goessling, Wolfram ^{[47
,48
,49
]}

Gudbjartsson, Daniel F. ^{[8
]}

Harris, Tamara B. ^{[50
]}

Hartikainen, Anna-Liisa ^{[51
]}

Heath, Simon ^{[52
]}

Hirschfield, Gideon M. ^{[53
,54
,55
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, London, England

[2] Imperial Coll Healthcare Natl Hlth Serv NHS Trust, London, England

[3] Ealing Hosp NHS Trust, Middlesex, England

[4] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England

[5] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Inst Clin Sci, London, England

[6] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, Struct Bioinformat Grp, London, England

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 AB Groningen, Netherlands

[8] deCODE Genet, Reykjavik, Iceland

[9] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[10] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[11] Netherlands Genom Initiat, Rotterdam, Netherlands

[12] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany

[13] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing, Peoples R China

[14] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[15] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[16] VU Univ Amsterdam VUA, Dept Biol Psychol, Amsterdam, Netherlands

[17] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan

[18] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands

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

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

[21] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[22] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[23] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England

[24] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland

[25] Univ Lausanne, Lausanne, Switzerland

[26] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England

[27] Univ Oulu, Inst Clin Med, Computat Med Res Grp, Oulu, Finland

[28] Univ Oulu, Bioctr, Oulu, Finland

[29] Univ Eastern Finland, Dept Biosci, Nucl Magnet Resonance NMR Metabon Lab, Kuopio, Finland

[30] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

[31] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[32] GlaxoSmithKline, Genet, King Of Prussia, PA USA

[33] Boston Univ, Sch Med, Boston, MA 02118 USA

[34] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

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

[36] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok, Thailand

[37] VUA, Amsterdam, Netherlands

[38] VUA Med Ctr, Amsterdam, Netherlands

[39] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[40] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[41] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA

[42] CHU Vaudois, IUMSP, CH-1011 Lausanne, Switzerland

[43] Univ Hosp Geneva, Dept Med, Geneva, Switzerland

[44] Lab Mjodd, Reykjavik, Iceland

[45] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England

[46] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17487 Greifswald, Germany

[47] Brigham & Womens Hosp, Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Div Genet, Boston, MA 02115 USA

[48] Brigham & Womens Hosp, Div Gastroenterol, Gastrointestinal Canc Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA

[49] Harvard Stem Cell Inst, Cambridge, MA USA

[50] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 11期

基金：

英国生物技术与生命科学研究理事会; 瑞士国家科学基金会; 英国惠康基金; 芬兰科学院; 瑞典研究理事会;

关键词：

C-REACTIVE PROTEIN; SALT EXPORT PUMP; RISK-FACTORS; HEPATOCELLULAR-CARCINOMA; SUSCEPTIBILITY LOCI; METABOLIC SYNDROME; GENETIC-VARIANTS; TYPE-2; TWIN; DISEASE;

D O I：

10.1038/ng.970

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

引用

页码：1131 / 1138

页数：8

共 72 条

[61] Biological, clinical and population relevance of 95 loci for blood lipids [J].

Teslovich, Tanya M. ;

Musunuru, Kiran ;

Smith, Albert V. ;

Edmondson, Andrew C. ;

Stylianou, Ioannis M. ;

Koseki, Masahiro ;

Pirruccello, James P. ;

Ripatti, Samuli ;

Chasman, Daniel I. ;

Willer, Cristen J. ;

Johansen, Christopher T. ;

Fouchier, Sigrid W. ;

Isaacs, Aaron ;

Peloso, Gina M. ;

Barbalic, Maja ;

Ricketts, Sally L. ;

Bis, Joshua C. ;

Aulchenko, Yurii S. ;

Thorleifsson, Gudmar ;

Feitosa, Mary F. ;

Chambers, John ;

Orho-Melander, Marju ;

Melander, Olle ;

Johnson, Toby ;

Li, Xiaohui ;

Guo, Xiuqing ;

Li, Mingyao ;

Cho, Yoon Shin ;

Go, Min Jin ;

Kim, Young Jin ;

Lee, Jong-Young ;

Park, Taesung ;

Kim, Kyunga ;

Sim, Xueling ;

Ong, Rick Twee-Hee ;

Croteau-Chonka, Damien C. ;

Lange, Leslie A. ;

Smith, Joshua D. ;

Song, Kijoung ;

Zhao, Jing Hua ;

Yuan, Xin ;

Luan, Jian'an ;

Lamina, Claudia ;

Ziegler, Andreas ;

Zhang, Weihua ;

Zee, Robert Y. L. ;

Wright, Alan F. ;

Witteman, Jacqueline C. M. ;

Wilson, James F. ;

Willemsen, Gonneke .

NATURE, 2010, 466 (7307) :707-713

[62] Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11 [J].

Van Mil, SWC ;

Van Der Woerd, WL ;

Van Der Brugge, G ;

Sturm, E ;

Jansen, PLM ;

Bull, LN ;

Van Den Berg, IET ;

Berger, R ;

Houwen, RHJ ;

Klomp, LWJ .

GASTROENTEROLOGY, 2004, 127 (02) :379-384

[63] Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis [J].

Voight, Benjamin F. ;

Scott, Laura J. ;

Steinthorsdottir, Valgerdur ;

Morris, Andrew P. ;

Dina, Christian ;

Welch, Ryan P. ;

Zeggini, Eleftheria ;

Huth, Cornelia ;

Aulchenko, Yurii S. ;

Thorleifsson, Gudmar ;

McCulloch, Laura J. ;

Ferreira, Teresa ;

Grallert, Harald ;

Amin, Najaf ;

Wu, Guanming ;

Willer, Cristen J. ;

Raychaudhuri, Soumya ;

McCarroll, Steve A. ;

Langenberg, Claudia ;

Hofmann, Oliver M. ;

Dupuis, Josee ;

Qi, Lu ;

Segre, Ayellet V. ;

van Hoek, Mandy ;

Navarro, Pau ;

Ardlie, Kristin ;

Balkau, Beverley ;

Benediktsson, Rafn ;

Bennett, Amanda J. ;

Blagieva, Roza ;

Boerwinkle, Eric ;

Bonnycastle, Lori L. ;

Bostrom, Kristina Bengtsson ;

Bravenboer, Bert ;

Bumpstead, Suzannah ;

Burtt, Noisel P. ;

Charpentier, Guillaume ;

Chines, Peter S. ;

Cornelis, Marilyn ;

Couper, David J. ;

Crawford, Gabe ;

Doney, Alex S. F. ;

Elliott, Katherine S. ;

Elliott, Amanda L. ;

Erdos, Michael R. ;

Fox, Caroline S. ;

Franklin, Christopher S. ;

Ganser, Martha ;

Gieger, Christian ;

Grarup, Niels .

NATURE GENETICS, 2010, 42 (07) :579-U155

[64] Genome-wide association study identifies genes for biomarkers of cardiovascular disease: Serum urate and dyslipiclemia [J].

Wallace, Chris ;

Newhouse, Stephen J. ;

Braund, Peter ;

Zhang, Feng ;

Tobin, Martin ;

Falchi, Mario ;

Ahmadi, Kourosh ;

Dobson, Richard J. ;

Maracano, Ana Carolina B. ;

Hajat, Cother ;

Burton, Paul ;

Deloukas, Panagiotis ;

Brown, Morris ;

Connell, John M. ;

Dominiczak, Anna ;

Lathrop, G. Mark ;

Webster, John ;

Farrall, Martin ;

Spector, Tim ;

Samani, Nilesh J. ;

Caulfield, Mark J. ;

Munroe, Patricia B. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (01) :139-149

[65] Idiosyncratic liver injury: Challenges and approaches [J].

Watkins, PB .

TOXICOLOGIC PATHOLOGY, 2005, 33 (01) :1-5

[66] Randomised controlled trial of the effects of physical activity feedback on awareness and behaviour in UK adults: the FAB study protocol [ISRCTN92551397] [J].

Watkinson, Clare ;

van Sluijs, Esther M. F. ;

Sutton, Stephen ;

Marteau, Theresa ;

Griffin, Simon J. .

BMC PUBLIC HEALTH, 2010, 10

[67] Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium [J].

Wolpin, Brian M. ;

Kraft, Peter ;

Xu, Mousheng ;

Steplowski, Emily ;

Olsson, Martin L. ;

Arslan, Alan A. ;

Bueno-de-Mesquita, H. Bas ;

Gross, Myron ;

Helzlsouer, Kathy ;

Jacobs, Eric J. ;

LaCroix, Andrea ;

Petersen, Gloria ;

Stolzenberg-Solomon, Rachael Z. ;

Zheng, Wei ;

Albanes, Demetrius ;

Allen, Naomi E. ;

Amundadottir, Laufey ;

Austin, Melissa A. ;

Boutron-Ruault, Marie-Christine ;

Buring, Julie E. ;

Canzian, Federico ;

Chanock, Stephen J. ;

Gaziano, J. Michael ;

Giovannucci, Edward L. ;

Hallmans, Goeran ;

Hankinson, Susan E. ;

Hoover, Robert N. ;

Hunter, David J. ;

Hutchinson, Amy ;

Jacobs, Kevin B. ;

Kooperberg, Charles ;

Mendelsohn, Julie B. ;

Michaud, Dominique S. ;

Overvad, Kim ;

Patel, Alpa V. ;

Sanchez, Maria-Jose ;

Sansbury, Leah ;

Shu, Xiao-Ou ;

Slimani, Nadia ;

Tobias, Geoffrey S. ;

Trichopoulos, Dimitrios ;

Vineis, Paolo ;

Visvanathan, Kala ;

Virtamo, Jarmo ;

Wactawski-Wende, Jean ;

Watters, Joanne ;

Yu, Kai ;

Zeleniuch-Jacquotte, Anne ;

Hartge, Patricia ;

Fuchs, Charles S. .

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2010, 19 (12) :3140-3149

[68] Characterization of systemic metabolic phenotypes associated with subclinical atherosclerosis [J].

Wurtz, Peter ;

Soininen, Pasi ;

Kangas, Antti J. ;

Makinen, Ville-Petteri ;

Groop, Per-Henrik ;

Savolainen, Markku J. ;

Juonala, Markus ;

Viikari, Jorma S. ;

Kahonen, Mika ;

Lehtimaki, Terho ;

Raitakari, Olli T. ;

Ala-Korpela, Mika .

MOLECULAR BIOSYSTEMS, 2011, 7 (02) :385-393

[69]

XU KC, 1992, AM J GASTROENTEROL, V87, P991

[70] Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes [J].

Yuan, Xin ;

Waterworth, Dawn ;

Perry, John R. B. ;

Lim, Noha ;

Song, Kijoung ;

Chambers, John C. ;

Zhang, Weihua ;

Vollenweider, Peter ;

Stirnadel, Heide ;

Johnson, Toby ;

Bergmann, Sven ;

Beckmann, Noam D. ;

Li, Yun ;

Ferrucci, Luigi ;

Melzer, David ;

Hernandez, Dena ;

Singleton, Andrew ;

Scott, James ;

Elliott, Paul ;

Waeber, Gerard ;

Cardon, Lon ;

Frayling, Timothy M. ;

Kooner, Jaspal S. ;

Mooser, Vincent .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 83 (04) :520-528

← 1 2 3 4 5 6 7 8 →