title: Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.
abstract: OBJECTIVE
  A recent genome-wide association study identified genetic polymorphism (rs738409 C>G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD.
  
  
  METHODS
  Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patient's phenotype.
  
  
  RESULTS
  The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.12-2.11 p = 0.008) and was, among ALD patients, significantly associated with steatosis (p = 0.048), fibrosis (p = 0.001), and greater risk of cirrhosis (p = 0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR = 2.08; 95% CI = 1.15-3.77; p = 0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p = 0.03) and negatively correlated with the hepatic venous pressure gradient (r = -0.41, p = 0.006).
  
  
  CONCLUSIONS
  In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD.
authors.affiliation: Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Trépo
authors.forename: Thierry
authors.initials: T
authors.lastname: Gustot
authors.forename: Delphine
authors.initials: D
authors.lastname: Degré
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemmers
authors.forename: Laurine
authors.initials: L
authors.lastname: Verset
authors.forename: Pieter
authors.initials: P
authors.lastname: Demetter
authors.forename: Romy
authors.initials: R
authors.lastname: Ouziel
authors.forename: Eric
authors.initials: E
authors.lastname: Quertinmont
authors.forename: Vincent
authors.initials: V
authors.lastname: Vercruysse
authors.forename: Leila
authors.initials: L
authors.lastname: Amininejad
authors.forename: Pierre
authors.initials: P
authors.lastname: Deltenre
authors.forename: Olivier
authors.initials: O
authors.lastname: Le Moine
authors.forename: Jacques
authors.initials: J
authors.lastname: Devière
authors.forename: Denis
authors.initials: D
authors.lastname: Franchimont
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
mesh_terms: D000328:Adult; D000368:Aged; D005235:Fatty Liver, Alcoholic / Q000208:ethnology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000208:ethnology / Q000235:genetics; D008104:Liver Cirrhosis, Alcoholic / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012307:Risk Factors; D044465:White People / Q000706:statistics & numerical data*; 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