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.
- 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 Schonfels, 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.
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/*genetics/pathology
- Male
- Non-alcoholic Fatty Liver Disease/epidemiology/genetics/pathology
- Odds Ratio
- Polymorphism, Single Nucleotide
- Prognosis
- Risk Assessment
- Sex Distribution
- alpha 1-Antitrypsin/*genetics
- *nash
- *serpina1
- *alcoholic liver disease
- *alpha1-antitrypsin deficiency
- *fibrosis