title: Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.
abstract: The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC.
  
  
  CONCLUSIONS
  Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.
authors.affiliation: Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Trépo
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bontempi
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Edmondo
authors.initials: E
authors.lastname: Falleti
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Samia
authors.initials: S
authors.lastname: Hamza
authors.forename: Stefano Ginanni
authors.initials: SG
authors.lastname: Corradini
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Burza
authors.forename: Erwan
authors.initials: E
authors.lastname: Guyot
authors.forename: Benedetta
authors.initials: B
authors.lastname: Donati
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Patrick
authors.initials: P
authors.lastname: Hillon
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Toniutto
authors.forename: Jean
authors.initials: J
authors.lastname: Henrion
authors.forename: Denis
authors.initials: D
authors.lastname: Franchimont
authors.forename: Jacques
authors.initials: J
authors.lastname: Devière
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Pierre
authors.initials: P
authors.lastname: Deltenre
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications; D008113:Liver Neoplasms / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D044465:White People; 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