title: Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.
abstract: Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76), nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes.
  
  
  CONCLUSIONS
  In patients with NAFLD, adiponutrin rs738409 C-->G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.
authors.affiliation: Department of Internal Medicine, Università degli Studi Milano, UO Medicina Interna 1B, Fondazione Ospedale Policlinico MaRE Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Serri
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Enrico
authors.initials: E
authors.lastname: Galmozzi
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.forename: Enrico
authors.initials: E
authors.lastname: Mozzi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Roviaro
authors.forename: Ester
authors.initials: E
authors.lastname: Vanni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
mesh_terms: D000328:Adult; D000368:Aged; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; 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