title: PNPLA3 in end-stage liver disease: alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival.
abstract: OBJECTIVE
  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.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany; Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Friedrich
authors.forename: Andreas
authors.initials: A
authors.lastname: Wannhoff
authors.forename: Stefan
authors.initials: S
authors.lastname: Kattner
authors.forename: Maik
authors.initials: M
authors.lastname: Brune
authors.forename: Johannes Roksund
authors.initials: JR
authors.lastname: Hov
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Weiss
authors.forename: Christoph
authors.initials: C
authors.lastname: Antoni
authors.forename: Matthias
authors.initials: M
authors.lastname: Dollinger
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Daniel Nils
authors.initials: DN
authors.lastname: Gotthardt
mesh_terms: D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008108:Liver Diseases, Alcoholic / Q000235:genetics* / Q000401:mortality; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality; D016031:Liver Transplantation; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D044465:White People / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: alcoholic liver disease; and therapy; cancers: biology; clinical; diagnosis; hepatocellular carcinoma; liver transplantation; metabolism.