title: Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance.
  
  
  METHODS
  702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients.
  
  
  RESULTS
  The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD.
  
  
  CONCLUSIONS
  The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.
authors.affiliation: Università degli Studi Milano, Policlinico MaRE IRCCS Hospital, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: L
authors.initials: L
authors.lastname: Valenti
authors.forename: R
authors.initials: R
authors.lastname: Rametta
authors.forename: A K
authors.initials: AK
authors.lastname: Daly
authors.forename: V
authors.initials: V
authors.lastname: Nobili
authors.forename: E
authors.initials: E
authors.lastname: Mozzi
authors.forename: J B S
authors.initials: JB
authors.lastname: Leathart
authors.forename: A
authors.initials: A
authors.lastname: Pietrobattista
authors.forename: A D
authors.initials: AD
authors.lastname: Burt
authors.forename: M
authors.initials: M
authors.lastname: Maggioni
authors.forename: A L
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: E
authors.initials: E
authors.lastname: Lattuada
authors.forename: M A
authors.initials: MA
authors.lastname: Zappa
authors.forename: G
authors.initials: G
authors.lastname: Roviaro
authors.forename: G
authors.initials: G
authors.lastname: Marchesini
authors.forename: C P
authors.initials: CP
authors.lastname: Day
authors.forename: S
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D011972:Receptor, Insulin / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases