Science and Research

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

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
Publication details
DOI: 10.1136/gutjnl-2018-316228
Journal: Gut
Pages: 1099-1107 
Number: 6
Work Type: Original
Location: Assoziierter Partner, ARCN, BREATH, TLRC
Disease Area: General Lung and Other
Partner / Member: LMU, LUH, MHH, UKHD, UKSH (Kiel)
Access-Number: 30068662
See publication on PubMed

DZL Engagements

chevron-down