PNPLA3 in end-stage liver disease: alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival.

Abstract

BACKGROUND AND AIMS:

The rs738409 variant (I148M) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end-stage liver disease has not been addressed yet.

METHODS:

The I148M polymorphism was genotyped in a well-characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant.

RESULTS:

The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P < 0.001) and associated with hepatocellular carcinoma (HCC) development (odds ratio [OR] = 2.399; 95% confidence interval [CI]: 1.292-4.455; P = 0.008) while not affecting the other liver disease entities. Time until hydropic decompensation (P = 0.04) and hepatic encephalopathy (P = 0.043) was significantly impaired for ALD patients carrying either one or two mutated G alleles. Actuarial survival free of liver transplantation was further reduced for ALD carriers of the I148M variant (CC = 30.7 months ± 7.9, 95% CI: 15.1-46.2 vs CG/GG: 17.1 months ± 3.3, 95% CI: 3.3-10.6; P = 0.012) compared with wild-type patients. Cox multivariate analysis identified the PNPLA3 I148M genotype as an independent predictor actuarial survival free of liver transplantation (OR = 1.77; 95% CI: 1.27-2.47; P = 0.001).

CONCLUSIONS:

In end-stage liver disease patients, we identified ALD to be predominantly affected by the PNPLA3 I148M variant resulting in an increased risk of HCC and reduced transplantation free survival. Genetic testing of the I148M genotype in ALD patients awaiting liver transplantation might be beneficial for these patients.

• Authors: Kilian Friedrich, Andreas Wannhoff, Stefan Kattner, Maik Brune, Johannes Roksund Hov, Karl Heinz Weiss, Christoph Antoni, Matthias Dollinger, Christoph Neumann-Haefelin, Thomas Seufferlein, Peter Schemmer, Peter Schirmacher, Wolfgang Stremmel, Daniel Nils Gotthardt
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 29 Issue 7 Pg. 1477-84 ( 2014) ISSN: 1440-1746 [Electronic] Australia
• PMID: 25273282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Chemical References

• Membrane Proteins
• Lipase
• adiponutrin, human

Topics

• Alleles
• Carcinoma, Hepatocellular (genetics, mortality)
• Cohort Studies
• Genetic Association Studies
• Genotype
• Humans
• Lipase (genetics)
• Liver Diseases, Alcoholic (genetics, mortality)
• Liver Neoplasms (genetics, mortality)
• Liver Transplantation
• Membrane Proteins (genetics)
• Mutation
• Polymorphism, Genetic (genetics)
• Retrospective Studies
• Severity of Illness Index
• Survival Rate
• White People (genetics)