Transmembrane 6 superfamily member 2 gene variant... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease

Dongiovanni, Paola1,†; Petta, Salvatore2,†; Maglio, Cristina3; Fracanzani, Anna Ludovica1; Pipitone, Rosaria2; Mozzi, Enrico1; Motta, Benedetta Maria3; Kaminska, Dorota4; Rametta, Raffaela1; Grimaudo, Stefania2; Pelusi, Serena1; Montalcini, Tiziana5; Alisi, Anna6; Maggioni, Marco1; Kärjä, Vesa4; Borén, Jan3; Käkelä, Pirjo4; Di Marco, Vito2; Xing, Chao7; Nobili, Valerio6; Dallapiccola, Bruno6; Craxi, Antonio2; Pihlajamäki, Jussi4; Fargion, Silvia1; Sjöström, Lars3; Carlsson, Lena M.3; Romeo, Stefano*,3,5; Valenti, Luca*,1

1Department of Pathophysiology and TransplantationUniversità degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico MilanoMilanItaly

2Department of GastroenterologyUniversità di PalermoPalermoItaly

3Wallenberg Laboratory, Department of Molecular and Clinical MedicineSahlgrenska Academy at the University of GothenburgGothenburgSweden

4Department of Public Health and Clinical Nutrition, Surgery and PathologyUniversity of Eastern FinlandKuopioFinland

5Clinical Nutrition Unit, Department of Medical and Surgical SciencesUniversity Magna GraeciaCatanzaroItaly

6Hepato‐Metabolic Unit and Scientific DirectionOspedale Bambin GesùRomaItaly

7Department of Clinical Science and Eugene McDermott Center for Human Growth & DevelopmentUT Southwestern Medical CenterDallasTX

*Address reprint requests to: Luca Valenti, M.D., Department of Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Pad. Granelli, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via F Sforza 35, 20122 Milano, Italy. E‐mail: [email protected]; fax: +390250320296 or Stefano Romeo, M.D., Ph.D., Bruna Stråket 16, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, S‐41345 Gothenburg, Sweden. E‐mail: [email protected]; fax: +46‐0‐31‐823762.

†These authors contributed equally to this work.

Abstract

Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very‐low‐density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more‐severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23‐2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20‐3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25‐0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39‐0.95). Conclusions: Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver. (Hepatology 2015;61:506‐514)