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

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)


Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 68

Pages Range: 1099-1107

Journal Issue: 6

DOI: 10.1136/gutjnl-2018-316228

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 ('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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Tecnológico de Monterrey (ITESM) MX Mexico (MX) Universität Salzburg (Paris Lodron Universität Salzburg) AT Austria (AT) Carol Davila University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie „Carol Davila” (UMF București) RO Romania (RO) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) European Association for the Study of the Liver EASL CH Switzerland (CH) Salzburger Landeskliniken (SALK) AT Austria (AT) Krankenhaus Jerusalem DE Germany (DE) Max-Planck-Institut für molekulare Zellbiologie und Genetik / Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE) Universität zu Köln DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Inselspital, Universitätsspital Bern CH Switzerland (CH) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) CH Switzerland (CH) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Otto-von-Guericke-Universität Magdeburg DE Germany (DE) Karl Landsteiner Gesellschaft AT Austria (AT) Universität Konstanz DE Germany (DE) Universität Regensburg DE Germany (DE) Evangelisches Krankenhaus Kalk DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Strnad, P., Buch, S., Hamesch, K., Fischer, J., Rosendahl, J., Schmelz, R.,... Trautwein, C. (2019). Heterozygous carriage of the alpha1-antitrypsin Pi∗Z variant increases the risk to develop liver cirrhosis. Gut, 68(6), 1099-1107. https://dx.doi.org/10.1136/gutjnl-2018-316228

MLA:

Strnad, Pavel, et al. "Heterozygous carriage of the alpha1-antitrypsin Pi∗Z variant increases the risk to develop liver cirrhosis." Gut 68.6 (2019): 1099-1107.

BibTeX: Download