A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

被引：450

作者：

Buch, Stephan ^{[1
]}

Stickel, Felix ^{[2
]}

Trepo, Eric ^{[3
,4
]}

Way, Michael ^{[5
,6
]}

Herrmann, Alexander ^{[1
]}

Nischalke, Hans Dieter ^{[7
]}

Brosch, Mario ^{[1
]}

Rosendahl, Jonas ^{[8
]}

Berg, Thomas ^{[8
]}

Ridinger, Monika ^{[9
,10
]}

Rietschel, Marcella ^{[11
]}

McQuillin, Andrew ^{[6
]}

Frank, Josef ^{[11
]}

Kiefer, Falk ^{[11
]}

Schreiber, Stefan ^{[12
]}

Lieb, Wolfgang ^{[13
,14
]}

Soyka, Michael ^{[15
]}

Semmo, Nasser ^{[16
]}

Aigner, Elmar ^{[17
]}

Datz, Christian ^{[17
]}

Schmelz, Renate ^{[1
]}

Brueckner, Stefan ^{[1
]}

Zeissig, Sebastian ^{[1
]}

Stephan, Anna-Magdalena ^{[1
]}

Wodarz, Norbert ^{[9
]}

Deviere, Jacques ^{[3
,4
]}

Clumeck, Nicolas ^{[18
]}

Sarrazin, Christoph ^{[19
]}

Lammert, Frank ^{[20
]}

Gustot, Thierry ^{[3
,4
]}

Deltenre, Pierre ^{[3
,21
,22
]}

Voelzke, Henry ^{[23
]}

Lerch, Markus M. ^{[24
]}

Mayerle, Julia ^{[24
]}

Eyer, Florian ^{[25
]}

Schafmayer, Clemens ^{[26
]}

Cichon, Sven ^{[27
]}

Noethen, Markus M. ^{[28
,29
]}

Nothnagel, Michael ^{[30
]}

Ellinghaus, David ^{[31
]}

Huse, Klaus ^{[32
]}

Franke, Andre ^{[31
]}

Zopf, Steffen ^{[33
]}

Hellerbrand, Claus ^{[34
]}

Moreno, Christophe ^{[3
,4
]}

Franchimont, Denis ^{[3
,4
]}

Morgan, Marsha Y. ^{[5
]}

Hampe, Jochen ^{[1
]}

机构：

[1] Tech Univ Dresden, Univ Hosp Dresden, Dept Med 1, Dresden, Germany

[2] Univ Zurich Hosp, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland

[3] Univ Libre Bruxelles, CUB Hop Erasme, Dept Gastroenterol Hepatopancreatol & Digest Onco, Brussels, Belgium

[4] Univ Libre Bruxelles, Lab Expt Gastroenterol, Brussels, Belgium

[5] UCL, UCL Inst Liver & Digest Hlth, Div Med, London, England

[6] UCL, Div Psychiat, Mol Psychiat Lab, London, England

[7] Univ Bonn, Dept Internal Med 1, Bonn, Germany

[8] Univ Hosp Leipzig, Sect Hepatol, Leipzig, Germany

[9] Univ Regensburg, Dept Psychiat & Psychotherapy, D-93053 Regensburg, Germany

[10] Psychiat Dienste Aargau, Psychiat Hlth Care Aargau, Windisch, Switzerland

[11] Heidelberg Univ, Fac Med Mannheim, Cent Inst Mental Hlth, Mannheim, Germany

[12] Univ Hosp Schleswig Holstein, Dept Internal Med 1, Kiel, Germany

[13] Univ Kiel, Inst Epidemiol, Kiel, Germany

[14] Univ Kiel, Biobank PopGen, Kiel, Germany

[15] Univ Munich, Hosp Psychiat, D-80539 Munich, Germany

[16] Inselspital Bern, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland

[17] Salzburg Univ, Teaching Hosp Paracelsus Private, Hosp Oberndorf, Dept Internal Med, A-5020 Salzburg, Austria

[18] Univ Libre Bruxelles, Ctr Hosp Le Domaine, Braine Lalleud, Belgium

[19] Univ Hosp Frankfurt, Dept Gastroenterol, Frankfurt, Germany

[20] Saarland Univ Hosp, Dept Med 2, Homburg, Germany

[21] Hop Jolimont, Serv Hepatogastroenterol, Haine St Paul, Belgium

[22] Univ Lausanne, CHU Vaudois, Div Gastroenterol & Hepatol, Lausanne, Switzerland

[23] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[24] Univ Med Greifswald, Dept Internal Med A, Greifswald, Germany

[25] Tech Univ Munich, Klinikum Rechts Isar, Dept Clin Toxicol, D-80290 Munich, Germany

[26] Univ Hosp Schleswig Holstein, Dept Gen & Thorac Surg, Kiel, Germany

[27] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland

[28] Univ Bonn, Inst Human Genet, Bonn, Germany

[29] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany

[30] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[31] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[32] Fritz Lipmann Inst Age Res FLI, Jena, Germany

[33] Univ Hosp Erlangen, Dept Internal Med 1, Erlangen, Germany

[34] Univ Hosp Regensburg, Dept Internal Med 1, Regensburg, Germany

来源：

NATURE GENETICS | 2015年 / 47卷 / 12期

基金：

瑞士国家科学基金会;

关键词：

LIVER-DISEASE; GENETIC PREDISPOSITION; CONFERS SUSCEPTIBILITY; END-POINTS; FIBROSIS; PROGRESSION; VARIANT; TRANSPLANTATION; POLYMORPHISM; GENOTYPE;

D O I：

10.1038/ng.3417

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world(1-3). We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 x 10(-9)) and TM6SF2 (P = 7.89 x 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 x 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

引用

页码：1443 / +

页数：8

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