RT Journal Article
SR Electronic
T1 Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1099
OP 1107
DO 10.1136/gutjnl-2018-316228
VO 68
IS 6
A1 Pavel Strnad
A1 Stephan Buch
A1 Karim Hamesch
A1 Janett Fischer
A1 Jonas Rosendahl
A1 Renate Schmelz
A1 Stefan Brueckner
A1 Mario Brosch
A1 Carolin V Heimes
A1 Vivien Woditsch
A1 David Scholten
A1 Hans Dieter Nischalke
A1 Sabina Janciauskiene
A1 Mattias Mandorfer
A1 Michael Trauner
A1 Michael J Way
A1 Andrew McQuillin
A1 Matthias C Reichert
A1 Marcin Krawczyk
A1 Markus Casper
A1 Frank Lammert
A1 Felix Braun
A1 Witigo von Schönfels
A1 Sebastian Hinz
A1 Greta Burmeister
A1 Claus Hellerbrand
A1 Andreas Teufel
A1 Alexandra Feldman
A1 Joern M Schattenberg
A1 Heike Bantel
A1 Anita Pathil
A1 Muenevver Demir
A1 Johannes Kluwe
A1 Tobias Boettler
A1 Monika Ridinger
A1 Norbert Wodarz
A1 Michael Soyka
A1 Marcella Rietschel
A1 Falk Kiefer
A1 Thomas Weber
A1 Silke Marhenke
A1 Arndt Vogel
A1 Holger Hinrichsen
A1 Ali Canbay
A1 Martin Schlattjan
A1 Katharina Sosnowsky
A1 Christoph Sarrazin
A1 Johann von Felden
A1 Andreas Geier
A1 Pierre Deltenre
A1 Bence Sipos
A1 Clemens Schafmayer
A1 Michael Nothnagel
A1 Elmar Aigner
A1 Christian Datz
A1 Felix Stickel
A1 Marsha Yvonne Morgan
A1 Jochen Hampe
A1 Thomas Berg
A1 Christian Trautwein
YR 2019
UL http://gut.bmj.com/content/68/6/1099.abstract
AB 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 The 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 NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).Conclusion The 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.