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

Journal article


Publication Details

Author(s): 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
Journal: Gut
Publication year: 2019
Volume: 68
Journal issue: 6
Pages range: 1099-1107
ISSN: 0017-5749
eISSN: 1468-3288


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.


FAU Authors / FAU Editors

Hellerbrand, Claus Prof. Dr.
Professur für Biochemie und Molekulare Pathobiologie


External institutions with authors

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


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.

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Last updated on 2019-23-05 at 07:34