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.
- alpha1-antitrypsin deficiency
- alcoholic liver disease
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PS, SB and KH contributed equally.
JH, TB and CT contributed equally.
Contributors Study concept and design: PS, KH, FS, MYM, JH, ThB and CT. Acquisition of data: PS, SB, KH, JR, JF, RS, SB, MB, CVH, VW, DS, HDN, MM, MT, MJW, AM, MCR, MK, FL, FB, WvS, CH, AT, AF, JMS, HB, AP, MD, JK, ToB, MCR, NW, MS, MR, FK, TW, SM, AV, HH, AC, MS, KS, ChS, JVF, SH, GB, AG, PD, BS, ClS, EA, CD, FS, MYM, JH and ThB. Analysis and interpretation of data: PS, SB, KH, MK, SJ, MM, BS, MN, EA, MYM, JH and CT. Drafting of the manuscript: PS, KH, SJ, MYM, JH, ThB and CT. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: PS, SB, KH and MN. Figures and tables: PS, SB, KH, MYM and CT. Obtained funding: PS, KH, HDN, FL, MM, MT, CS, FS, MYM, JH and CT. Study supervision: PS, SB, KH, EA, FS, MYM, JH, ThB and CT. All authors had full access to all of the data and approved the final version of this manuscript. All authors can take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by the EASL registry grant on alpha1-antitrypsin-related liver disease (to PS and CT), the Interdisciplinary Center for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University (to PS), the Else Kröner Excellence Fellowship (to PS), the Deutsche Forschungsgemeinschaft (DFG) consortium SFB/TRR57 ‘Liver fibrosis’ (to PS and CT), the German Liver Foundation (to KH), the German Gastroenterological Association (to KH), the German Ministry of Education and Research through the Virtual Liver Network (to JH), the Swiss National Funds (grant 310030_138747 to FS), the Deutsche Krebshilfe (to HDN), the Liver Systems Medicine (BMBF LiSyM 031L0051 to FL and CT), the Joseph-Skoda Award of the Austrian Society of Internal Medicine (to MM), the European Union 7th framework programme (/FP7/2007-2013, project ‘FLIP’ to MT). The British-Irish research effort was funded by a PhD studentship award jointly funded by University College London and an anonymous donor (to MYM). The non-alcoholic fatty liver disease cohort was supported by the German Ministry of Education and Research through the Virtual Liver and Liver Systems Medicine (LiSyM) Projects and through institutional funds from the Medical Faculty of the University of Kiel (to CS).
Disclaimer We attest that we did not use any copyright-protected material in our manuscript. No writing assistance was provided.
Competing interests None declared.
Patient consent Not required.
Ethics approval The study protocol was approved by the responsible local ethics committee of participating multiple centres in Germany, Switzerland, Austria and Great Britain.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Patient level data, technical appendix and statistical code are available from the corresponding author and can be shared upon request. An informed consent for data sharing was not obtained from study participants, but the presented data are anonymised and the risk of identification is low.
Correction notice This article has been corrected since it published Online First. Figure 5B has been corrected.