Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

被引：96

作者：

Strnad, Pavel ^{[1
,2
]}

Buch, Stephan ^{[3
]}

Hamesch, Karim ^{[1
,2
]}

Fischer, Janett ^{[4
]}

Rosendahl, Jonas ^{[4
,5
]}

Schmelz, Renate ^{[3
]}

Brueckner, Stefan ^{[3
]}

Brosch, Mario ^{[3
]}

Heimes, Carolin V. ^{[1
]}

Woditsch, Vivien ^{[1
]}

Scholten, David ^{[1
]}

Nischalke, Hans Dieter ^{[6
]}

Janciauskiene, Sabina ^{[7
]}

Mandorfer, Mattias ^{[8
]}

Trauner, Michael ^{[8
]}

Way, Michael J. ^{[9
,10
]}

McQuillin, Andrew ^{[10
]}

Reichert, Matthias C. ^{[11
]}

Krawczyk, Marcin ^{[11
,12
]}

Casper, Markus ^{[11
]}

Lammert, Frank ^{[13
]}

von Schoenfels, Witigo ^{[13
]}

Hinz, Sebastian ^{[13
]}

Burmeister, Greta ^{[13
]}

Hellerbrand, Claus ^{[14
]}

Teufel, Andreas ^{[15
]}

Feldman, Alexandra ^{[16
]}

Schattenberg, Joern M. ^{[17
]}

Bantel, Heike ^{[18
]}

Pathil, Anita ^{[19
]}

Demir, Muenevver ^{[20
]}

Kluwe, Johannes ^{[21
]}

Boettler, Tobias ^{[22
]}

Ridinger, Monika ^{[23
]}

Wodarz, Norbert ^{[24
]}

Soyka, Michael ^{[25
]}

Rietschel, Marcella ^{[26
]}

Kiefer, Falk ^{[26
]}

Weber, Thomas ^{[27
]}

Marhenke, Silke ^{[18
]}

Vogel, Arndt ^{[18
]}

Hinrichsen, Holger ^{[28
]}

Canbay, Ali ^{[29
,30
]}

Schlattjan, Martin ^{[30
]}

Sosnowsky, Katharina ^{[31
]}

Sarrazin, Christoph ^{[31
]}

von Felden, Johann ^{[21
]}

Geier, Andreas ^{[32
]}

Deltenre, Pierre ^{[33
,34
]}

Sipos, Bence ^{[35
]}

机构：

[1] Univ Hosp RWTH Aachen, Med Clin Gastroenterol Metab Dis & Intens Care 3, Aachen, Germany

[2] EASL, European Reference Network ERN Rare Liver, Coordinating Ctr Alpha1 Antitrypsin Deficiency Re, Aachen, Germany

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

[4] Univ Hosp Leipzig, Dept Internal Med, Sect Hepatol, D-04103 Leipzig, Germany

[5] Martin Luther Univ Halle Wittenberg, Univ Hosp Halle, Dept Internal Med 1, Halle, Germany

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

[7] Hannover Med Sch, German Ctr Lung Res DZL, Clin Pneumol, Hannover, Germany

[8] Med Univ Vienna, Clin Gastroenterol & Hepatol, Vienna, Austria

[9] UCL, Div Med, Inst Liver & Digest Hlth, Royal Free Campus, London, England

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

[11] Saarland Univ, Med Ctr, Dept Med 2, Homburg, Germany

[12] Med Univ Warsaw, Dept Gen Transplantat & Liver Surg, Lab Metab Liver Dis, Warsaw, Poland

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

[14] Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Erlangen, Germany

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

[16] Univ Hosp Salzburg, Dept Internal Med 1, Salzburg, Austria

[17] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Dept Med 1, Mainz, Germany

[18] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[19] Heidelberg Univ, Dept Internal Med Gastroenterol & Hepatol 4, Heidelberg, Germany

[20] Univ Hosp Cologne, Clin Gastroenterol & Hepatol, Cologne, Germany

[21] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med 1, Hamburg, Germany

[22] Univ Freiburg, Fac Med, Med Ctr, Dept Med 2, Freiburg, Germany

[23] Univ Konstanz, Dept Psychol, Constance, Germany

[24] Univ Regensburg, Dept Psychiat & Psychotherapy, Regensburg, Germany

[25] Ludwig Maximilians Univ Munchen, Psychiat Hosp, Munich, Germany

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

[27] Univ Hosp Bern, Dept Clin Res, Bern, Switzerland

[28] Univ Hosp Kiel, Dept Gastroenterol, Kiel, Germany

[29] Otto Von Guericke Univ, Dept Gastroenterol Hepatol & Infect Dis, Magdeburg, Germany

[30] Univ Duisburg Essen, Dept Gastroenterol & Hepatol, Essen, Germany

[31] JW Goethe Univ Hosp Frankfurt, Dept Internal Med 1, Frankfurt, Germany

[32] Univ Hosp Wuerzburg, Dept Med 2, Div Hepatol, Wurzburg, Germany

[33] Univ Lausanne, Ctr Hosp Univ Vaudois, Div Gastroenterol & Hepatol, Lausanne, Switzerland

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

[35] Univ Tubingen, Inst Pathol, Tubingen, Germany

[36] Univ Cologne, Cologne Ctr Genom, Cologne, Germany

[37] Paracelsus Private Univ Salzburg, Teaching Hosp, Hosp Oberndorf, Dept Internal Med, Oberndorf, Austria

[38] Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Zurich, Switzerland

来源：

GUT | 2019年 / 68卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

MZ ALPHA-1-ANTITRYPSIN DEFICIENCY; GENOME-WIDE ASSOCIATION; TM6SF2; RS58542926; HEPATIC-FIBROSIS; HIGH PREVALENCE; DISEASE; ALPHA(1)-ANTITRYPSIN; ADULTS; ALCOHOL; PNPLA3;

D O I：

10.1136/gutjnl-2018-316228

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (' Pi* Z' and ' Pi* S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi* Z and Pi* S variants was performed. Results T he Pi* Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p< 0.0001). Accordingly, the Pi* Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi* Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p< 0.0001). Correspondingly, alcohol misusers carrying the Pi* Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi* S variant was not associated with NAFLDrelated cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion T he Pi* Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi* S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi* Z carriers, this finding should be considered in genetic counselling of affected individuals.

引用

页码：1099 / 1107

页数：9

共 49 条

[1] A Role for Low Hepatic Copper Concentrations in Nonalcoholic Fatty Liver Disease [J].

Aigner, Elmar ;

Strasser, Michael ;

Haufe, Heike ;

Sonnweber, Thomas ;

Hohla, Florian ;

Stadlmayr, Andreas ;

Solioz, Marc ;

Tilg, Herbert ;

Patsch, Wolfgang ;

Weiss, Guenter ;

Stickel, Felix ;

Datz, Christian .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2010, 105 (09) :1978-1985

[2] Genotyping diagnosis of alpha-1 antitrypsin deficiency in Saudi adults with liver cirrhosis [J].

Al-Jameil, Noura ;

Hassan, Amina A. ;

Buhairan, Ahlam ;

Hassanato, Rana ;

Isac, Sree R. ;

Al-Otaiby, Maram ;

Al-Maarik, Basmah ;

Al-Ajeyan, Iman .

MEDICINE, 2017, 96 (06)

[3] American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency [J].

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2003, 168 (07) :818-855

[4] Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease [J].

Anstee, Quentin M. ;

Seth, Devanshi ;

Day, Christopher P. .

GASTROENTEROLOGY, 2016, 150 (08) :1728-+

[5] Endoplasmic reticulum proteostasis in hepatic steatosis [J].

Baiceanu, Andrei ;

Mesdom, Pierre ;

Lagouge, Marie ;

Foufelle, Fabienne .

NATURE REVIEWS ENDOCRINOLOGY, 2016, 12 (12) :710-+

[6] HETEROZYGOUS MZ ALPHA-1-ANTITRYPSIN DEFICIENCY IN ADULTS WITH CHRONIC LIVER-DISEASE [J].

BELL, H ;

SCHRUMPF, E ;

FAGERHOL, MK .

SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 1990, 25 (08) :788-792

[7] Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update [J].

Blanco, Ignacio ;

Bueno, Patricia ;

Diego, Isidro ;

Perez-Holanda, Sergio ;

Casas-Maldonado, Francisco ;

Esquinas, Cristina ;

Miravitlles, Marc .

INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, 2017, 12 :561-569

[8] A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis [J].

Buch, Stephan ;

Stickel, Felix ;

Trepo, Eric ;

Way, Michael ;

Herrmann, Alexander ;

Nischalke, Hans Dieter ;

Brosch, Mario ;

Rosendahl, Jonas ;

Berg, Thomas ;

Ridinger, Monika ;

Rietschel, Marcella ;

McQuillin, Andrew ;

Frank, Josef ;

Kiefer, Falk ;

Schreiber, Stefan ;

Lieb, Wolfgang ;

Soyka, Michael ;

Semmo, Nasser ;

Aigner, Elmar ;

Datz, Christian ;

Schmelz, Renate ;

Brueckner, Stefan ;

Zeissig, Sebastian ;

Stephan, Anna-Magdalena ;

Wodarz, Norbert ;

Deviere, Jacques ;

Clumeck, Nicolas ;

Sarrazin, Christoph ;

Lammert, Frank ;

Gustot, Thierry ;

Deltenre, Pierre ;

Voelzke, Henry ;

Lerch, Markus M. ;

Mayerle, Julia ;

Eyer, Florian ;

Schafmayer, Clemens ;

Cichon, Sven ;

Noethen, Markus M. ;

Nothnagel, Michael ;

Ellinghaus, David ;

Huse, Klaus ;

Franke, Andre ;

Zopf, Steffen ;

Hellerbrand, Claus ;

Moreno, Christophe ;

Franchimont, Denis ;

Morgan, Marsha Y. ;

Hampe, Jochen .

NATURE GENETICS, 2015, 47 (12) :1443-+

[9] Pi Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis [J].

Cacciottolo, Tessa M. ;

Gelson, William T. H. ;

Maguire, Gerald ;

Davies, Susan E. ;

Griffiths, William J. H. .

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 2014, 26 (04) :412-417

[10] Mechanisms of disease -: Alpha1-antitrypsin deficiency -: A model for conformational diseases [J].

Carrell, RW ;

Lomas, DA .

NEW ENGLAND JOURNAL OF MEDICINE, 2002, 346 (01) :45-53

← 1 2 3 4 5 →