Strnad P Buch S Hamesch K Fischer J Rosendahl J Schmelz R Brueckner S Brosch M Heimes CV Woditsch V Scholten D Nischalke HD Janciauskiene S Mandorfer M Trauner M Way MJ McQuillin A Reichert MC Krawczyk M Casper M Lammert F Braun F von Schönfels W Hinz S Burmeister G Hellerbrand C Teufel A Feldman A Schattenberg JM Bantel H Pathil A Demir M Kluwe J Boettler T Ridinger M Wodarz N Soyka M Rietschel M Kiefer F Weber T Marhenke S Vogel A Hinrichsen H Canbay A Schlattjan M Sosnowsky K Sarrazin C von Felden J Geier A Deltenre P Sipos B Schafmayer C Nothnagel M Aigner E Datz C Stickel F Morgan MY Hampe J Berg T Trautwein C 2019 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. application/pdf https://sonar.ch/global/documents/278764 eng info:eu-repo/semantics/altIdentifier/doi/10.1136/gutjnl-2018-316228 info:eu-repo/semantics/altIdentifier/pmid/30068662 info:eu-repo/semantics/openAccess Gut. - 2019 NASH SERPINA1 alcoholic liver disease alpha1-antitrypsin deficiency fibrosis Age Distribution Austria Biopsy, Needle Case-Control Studies Confidence Intervals Female Genetic Carrier Screening Genetic Predisposition to Disease Genetic Variation Germany Heterozygote Humans Immunohistochemistry Incidence Liver Cirrhosis, Alcoholic Male Non-alcoholic Fatty Liver Disease Odds Ratio Polymorphism, Single Nucleotide Prognosis Risk Assessment Sex Distribution alpha 1-Antitrypsin Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. http://purl.org/coar/resource_type/c_6501