TY - JOUR T1 - Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis JF - Gut JO - Gut SP - 1099 LP - 1107 DO - 10.1136/gutjnl-2018-316228 VL - 68 IS - 6 AU - Pavel Strnad AU - Stephan Buch AU - Karim Hamesch AU - Janett Fischer AU - Jonas Rosendahl AU - Renate Schmelz AU - Stefan Brueckner AU - Mario Brosch AU - Carolin V Heimes AU - Vivien Woditsch AU - David Scholten AU - Hans Dieter Nischalke AU - Sabina Janciauskiene AU - Mattias Mandorfer AU - Michael Trauner AU - Michael J Way AU - Andrew McQuillin AU - Matthias C Reichert AU - Marcin Krawczyk AU - Markus Casper AU - Frank Lammert AU - Felix Braun AU - Witigo von Schönfels AU - Sebastian Hinz AU - Greta Burmeister AU - Claus Hellerbrand AU - Andreas Teufel AU - Alexandra Feldman AU - Joern M Schattenberg AU - Heike Bantel AU - Anita Pathil AU - Muenevver Demir AU - Johannes Kluwe AU - Tobias Boettler AU - Monika Ridinger AU - Norbert Wodarz AU - Michael Soyka AU - Marcella Rietschel AU - Falk Kiefer AU - Thomas Weber AU - Silke Marhenke AU - Arndt Vogel AU - Holger Hinrichsen AU - Ali Canbay AU - Martin Schlattjan AU - Katharina Sosnowsky AU - Christoph Sarrazin AU - Johann von Felden AU - Andreas Geier AU - Pierre Deltenre AU - Bence Sipos AU - Clemens Schafmayer AU - Michael Nothnagel AU - Elmar Aigner AU - Christian Datz AU - Felix Stickel AU - Marsha Yvonne Morgan AU - Jochen Hampe AU - Thomas Berg AU - Christian Trautwein Y1 - 2019/06/01 UR - http://gut.bmj.com/content/68/6/1099.abstract N2 - 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. ER -