title: The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.
abstract: BACKGROUND
  An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC).
  
  
  METHODS
  We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection.
  
  
  RESULTS
  PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68-42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24-6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50-11.52; p = 0.006).
  
  
  CONCLUSIONS
  The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Cordula
authors.initials: C
authors.lastname: Berger
authors.forename: Carolin
authors.initials: C
authors.lastname: Luda
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Martin
authors.initials: M
authors.lastname: Coenen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Natascha
authors.initials: N
authors.lastname: Vidovic
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006526:Hepatitis C / Q000150:complications* / Q000235:genetics; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000150:complications* / Q000235:genetics; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications* / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D012307:Risk Factors; D044465:White People; D055815:Young Adult; 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
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