Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
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Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. / Strnad, Pavel; Buch, Stephan; Hamesch, Karim; Fischer, Janett; Rosendahl, Jonas; Schmelz, Renate; Brueckner, Stefan; Brosch, Mario; Heimes, Carolin V; Woditsch, Vivien; Scholten, David; Nischalke, Hans Dieter; Janciauskiene, Sabina; Mandorfer, Mattias; Trauner, Michael; Way, Michael J; McQuillin, Andrew; Reichert, Matthias C; Krawczyk, Marcin; Casper, Markus; Lammert, Frank; Braun, Felix; von Schönfels, Witigo; Hinz, Sebastian; Burmeister, Greta; Hellerbrand, Claus; Teufel, Andreas; Feldman, Alexandra; Schattenberg, Joern M; Bantel, Heike; Pathil, Anita; Demir, Muenevver; Kluwe, Johannes; Boettler, Tobias; Ridinger, Monika; Wodarz, Norbert; Soyka, Michael; Rietschel, Marcella; Weber, Thomas; Marhenke, Silke; Vogel, Arndt; Hinrichsen, Holger; Canbay, Ali; Schlattjan, Martin; Sosnowsky, Katharina; Sarrazin, Christoph; von Felden, Johann; Geier, Andreas; Deltenre, Pierre; Sipos, Bence; Schafmayer, Clemens; Nothnagel, Michael; Aigner, Elmar; Datz, Christian; Stickel, Felix; Morgan, Marsha Yvonne; Hampe, Jochen; Berg, Thomas; Trautwein, Christian.
In: GUT, Vol. 68, No. 6, 06.2019, p. 1099-1107.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -