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Type: Journal article
Title: Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease
Author: Dongiovanni, P.
Valenti, L.
Rametta, R.
Daly, A.
Nobili, V.
Mozzi, E.
Leathart, J.
Pietrobattista, A.
Burt, A.
Maggioni, M.
Fracanzani, A.
Lattuada, E.
Zappa, M.
Roviaro, G.
Marchesini, G.
Day, C.
Fargion, S.
Citation: Gut, 2010; 59(2):267-273
Publisher: British Med Journal Publ Group
Issue Date: 2010
ISSN: 0017-5749
Statement of
P Dongiovanni, L Valenti, R Rametta, A K Daly, V Nobili, E Mozzi, J B S Leathart, A Pietrobattista, A D Burt, M Maggioni, A L Fracanzani, E Lattuada, M A Zappa, G Roviaro, G Marchesini, C P Day, S Fargion
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.
Keywords: Humans
Fatty Liver
Insulin Resistance
Genetic Predisposition to Disease
Phosphoric Diester Hydrolases
Receptor, Insulin
Severity of Illness Index
Signal Transduction
Polymorphism, Single Nucleotide
Middle Aged
Insulin Receptor Substrate Proteins
Rights: Copyright status unknown
DOI: 10.1136/gut.2009.190801
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