title: Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.
abstract: OBJECTIVE
  Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD.
  
  
  METHODS
  PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD.
  
  
  RESULTS
  Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001).
  
  
  CONCLUSIONS
  Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: G L
authors.initials: GL
authors.lastname: Patman
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J B S
authors.initials: JB
authors.lastname: Leathart
authors.affiliation: University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
authors.forename: A-C
authors.initials: AC
authors.lastname: Piguet
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Burt
authors.affiliation: University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
authors.forename: J-F
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C P
authors.initials: CP
authors.lastname: Day
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Daly
authors.affiliation: Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK. Electronic address: helen.reeves@ncl.ac.uk.
authors.forename: H L
authors.initials: HL
authors.lastname: Reeves
authors.affiliation: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Q M
authors.initials: QM
authors.lastname: Anstee
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; 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: Gene; HCC; Hepatocellular carcinoma; NAFLD; NASH; PNPLA3; Steatohepatitis