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Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease
  1. P Dongiovanni1,
  2. L Valenti1,
  3. R Rametta1,
  4. A K Daly2,
  5. V Nobili3,
  6. E Mozzi1,
  7. J B S Leathart2,
  8. A Pietrobattista3,
  9. A D Burt2,
  10. M Maggioni4,
  11. A L Fracanzani1,
  12. E Lattuada1,
  13. M A Zappa1,
  14. G Roviaro1,
  15. G Marchesini5,
  16. C P Day2,
  17. S Fargion1
  1. 1Università degli Studi Milano, Policlinico MaRE IRCCS Hospital, Milan, Italy
  2. 2Institute of Cellular Medicine, Newcastle University, UK
  3. 3Liver Unit, “Bambino Gesù” Children's Hospital and Research Center, Rome, Italy
  4. 4Unitá Operative Anatomia patologica, Ospedale Sam Paulo and Policlinico IRCCS Milan, Italy
  5. 5Universitá Alma Mater, Bologna, Italy
  1. Correspondence to Dr L Valenti, Centro per lo Studio delle Malattie del Fegato e del Metabolismo, Department of Internal Medicine, UO Medicina Interna 1B, University of Milano, Ospedale Policlinico Mangiagalli e Regina Elena Fondazione IRCCS, Via F Sforza 35, 20122 Milano, Italy; luca.valenti{at}unimi.it

Abstract

Background/aims 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.

Patients and 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 ∼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.

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Footnotes

  • An additional table is published online only at http://gut.bmj.com/content/vol59/issue2

  • PD and LV contributed equally to this work.

  • Funding The work was supported by the following grants: FIRST Università di Milano 2007, 2008 (LV, SF, ALF); Ricerca corrente Ospedale Maggiore Policlinico 2006 and 2008 (LV, SF); and Centro per lo Studio delle Malattie del Fegato e del Metabolismo.

  • Competing interests None.

  • Ethics approval Ospedale Policlinico MaRE IRCCS approved this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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