title: Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.
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.
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Petta
authors.forename: Cristina
authors.initials: C
authors.lastname: Maglio
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Rosaria
authors.initials: R
authors.lastname: Pipitone
authors.forename: Enrico
authors.initials: E
authors.lastname: Mozzi
authors.forename: Benedetta Maria
authors.initials: BM
authors.lastname: Motta
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.forename: Serena
authors.initials: S
authors.lastname: Pelusi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Montalcini
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Vesa
authors.initials: V
authors.lastname: Kärjä
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.forename: Vito
authors.initials: V
authors.lastname: Di Marco
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxi
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Lars
authors.initials: L
authors.lastname: Sjöström
authors.forename: Lena M
authors.initials: LM
authors.lastname: Carlsson
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D000328:Adult; D001706:Biopsy; D002340:Carotid Artery Diseases / Q000235:genetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000150:complications
chemical_list: D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C419195:TM6SF2 protein, human