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

TY - JOUR

T1 - Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

AU - Strnad, Pavel

AU - Buch, Stephan

AU - Hamesch, Karim

AU - Fischer, Janett

AU - Rosendahl, Jonas

AU - Schmelz, Renate

AU - Brueckner, Stefan

AU - Brosch, Mario

AU - Heimes, Carolin V

AU - Woditsch, Vivien

AU - Scholten, David

AU - Nischalke, Hans Dieter

AU - Janciauskiene, Sabina

AU - Mandorfer, Mattias

AU - Trauner, Michael

AU - Way, Michael J

AU - McQuillin, Andrew

AU - Reichert, Matthias C

AU - Krawczyk, Marcin

AU - Casper, Markus

AU - Lammert, Frank

AU - Braun, Felix

AU - von Schönfels, Witigo

AU - Hinz, Sebastian

AU - Burmeister, Greta

AU - Hellerbrand, Claus

AU - Teufel, Andreas

AU - Feldman, Alexandra

AU - Schattenberg, Joern M

AU - Bantel, Heike

AU - Pathil, Anita

AU - Demir, Muenevver

AU - Kluwe, Johannes

AU - Boettler, Tobias

AU - Ridinger, Monika

AU - Wodarz, Norbert

AU - Soyka, Michael

AU - Rietschel, Marcella

AU - Weber, Thomas

AU - Marhenke, Silke

AU - Vogel, Arndt

AU - Hinrichsen, Holger

AU - Canbay, Ali

AU - Schlattjan, Martin

AU - Sosnowsky, Katharina

AU - Sarrazin, Christoph

AU - von Felden, Johann

AU - Geier, Andreas

AU - Deltenre, Pierre

AU - Sipos, Bence

AU - Schafmayer, Clemens

AU - Nothnagel, Michael

AU - Aigner, Elmar

AU - Datz, Christian

AU - Stickel, Felix

AU - Morgan, Marsha Yvonne

AU - Hampe, Jochen

AU - Berg, Thomas

AU - Trautwein, Christian

N1 - © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2019/6

Y1 - 2019/6

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.

AB - 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.

KW - Journal Article

U2 - 10.1136/gutjnl-2018-316228

DO - 10.1136/gutjnl-2018-316228

M3 - SCORING: Journal article

C2 - 30068662

VL - 68

SP - 1099

EP - 1107

JO - GUT

JF - GUT

SN - 0017-5749

IS - 6

ER -