@article {Strnad1099, author = {Pavel Strnad and Stephan Buch and Karim Hamesch and Janett Fischer and Jonas Rosendahl and Renate Schmelz and Stefan Brueckner and Mario Brosch and Carolin V Heimes and Vivien Woditsch and David Scholten and Hans Dieter Nischalke and Sabina Janciauskiene and Mattias Mandorfer and Michael Trauner and Michael J Way and Andrew McQuillin and Matthias C Reichert and Marcin Krawczyk and Markus Casper and Frank Lammert and Felix Braun and Witigo von Sch{\"o}nfels and Sebastian Hinz and Greta Burmeister and Claus Hellerbrand and Andreas Teufel and Alexandra Feldman and Joern M Schattenberg and Heike Bantel and Anita Pathil and Muenevver Demir and Johannes Kluwe and Tobias Boettler and Monika Ridinger and Norbert Wodarz and Michael Soyka and Marcella Rietschel and Falk Kiefer and Thomas Weber and Silke Marhenke and Arndt Vogel and Holger Hinrichsen and Ali Canbay and Martin Schlattjan and Katharina Sosnowsky and Christoph Sarrazin and Johann von Felden and Andreas Geier and Pierre Deltenre and Bence Sipos and Clemens Schafmayer and Michael Nothnagel and Elmar Aigner and Christian Datz and Felix Stickel and Marsha Yvonne Morgan and Jochen Hampe and Thomas Berg and Christian Trautwein}, title = {Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis}, volume = {68}, number = {6}, pages = {1099--1107}, year = {2019}, doi = {10.1136/gutjnl-2018-316228}, publisher = {BMJ Publishing Group}, abstract = {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 ({\textquoteleft}Pi*Z{\textquoteright} and {\textquoteleft}Pi*S{\textquoteright}), present in up to 10\% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.Design We analysed multicentric case{\textendash}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\%{\textendash}4\% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/68/6/1099}, eprint = {https://gut.bmj.com/content/68/6/1099.full.pdf}, journal = {Gut} }