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

Details

Serval ID
serval:BIB_AAE1B071724A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.
Journal
Gut
Author(s)
Strnad P., Buch S., Hamesch K., Fischer J., Rosendahl J., Schmelz R., Brueckner S., Brosch M., Heimes C.V., Woditsch V., Scholten D., Nischalke H.D., Janciauskiene S., Mandorfer M., Trauner M., Way M.J., McQuillin A., Reichert M.C., Krawczyk M., Casper M., Lammert F., Braun F., von Schönfels W., Hinz S., Burmeister G., Hellerbrand C., Teufel A., Feldman A., Schattenberg J.M., 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 M.Y., Hampe J., Berg T., Trautwein C.
ISSN
1468-3288 (Electronic)
ISSN-L
0017-5749
Publication state
Published
Issued date
06/2019
Peer-reviewed
Oui
Volume
68
Number
6
Pages
1099-1107
Language
english
Notes
Publication types: Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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.
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)).
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.
Keywords
Age Distribution, Austria, Biopsy, Needle, Case-Control Studies, Confidence Intervals, Female, Genetic Carrier Screening, Genetic Predisposition to Disease/epidemiology, Genetic Variation, Germany, Heterozygote, Humans, Immunohistochemistry, Incidence, Liver Cirrhosis, Alcoholic/epidemiology, Liver Cirrhosis, Alcoholic/genetics, Liver Cirrhosis, Alcoholic/pathology, Male, Non-alcoholic Fatty Liver Disease/epidemiology, Non-alcoholic Fatty Liver Disease/genetics, Non-alcoholic Fatty Liver Disease/pathology, Odds Ratio, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, alpha 1-Antitrypsin/genetics, NASH, SERPINA1, alcoholic liver disease, alpha1-antitrypsin deficiency, fibrosis
Pubmed
Web of science
Create date
07/08/2018 8:50
Last modification date
21/08/2019 5:36
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