title: Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients.
abstract: Steatosis and inherited host factors influence liver damage progression in chronic hepatitis C (CHC). The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant increases liver fat and risk of progressive steatohepatitis by interfering with lipoprotein secretion. Our aim was to determine whether the E167K variant affects histological severity of steatosis, necroinflammation, and fibrosis in a cross-sectional cohort of 815 Italian therapy-naïve CHC patients. The association with clinically significant fibrosis was replicated in 645 Swiss/German patients. The TM6SF2 E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients. The E167K variant was detected in 69 (9%) Italian patients and was associated with more severe steatosis, independently of confounders (P = 0.038). The association between E167K and steatosis severity was present in patients not infected by genotype 3 (G3) HCV (P = 0.031), but not in those infected by G3 HCV (P = 0.58). Furthermore, the E167K variant was associated with more severe necroinflammation (Ishak grade; adjusted P = 0.037) and nearly associated with more severe fibrosis (Ishak stage; adjusted P = 0.058). At multivariate logistic regression analysis, the E167K variant was independently associated with histologically probable or definite cirrhosis (Ishak stage S6; odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.18-3.93; P = 0.010). After further conditioning for steatosis and necroinflammation, the E167K variant remained associated with cirrhosis (OR, 3.15; 95% CI: 1.60-5.99; P < 0.001). In Swiss/German patients, the E167K variant was independently associated with clinically significant fibrosis Metavir stage F2-F4 (OR, 1.81; 95% CI: 1.12-3.02; P = 0.016).
  
  
  CONCLUSIONS
  TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis in patients with CHC.
authors.affiliation: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Milano
authors.affiliation: Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Aghemo
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Rosellina Margherita
authors.initials: RM
authors.lastname: Mancina
authors.affiliation: Department of Gastroenterology and Rheumatology, Section Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: De Nicola
authors.affiliation: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Ambrosio
authors.affiliation: Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: Virology program, Istituto Nazionale di Genetica Molecolare "Romeo e Enrica Invernizzi,", Milan, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.affiliation: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Department of Gastroenterology and Rheumatology, Section Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Hepatology, University Hospital Zürich, University of Zürich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.affiliation: Molecular Gastroenterology and Hepatology, University Hospital of Dresden, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.|Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D016021:Epidemiologic Studies; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D005355:Fibrosis; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D012720:Severity of Illness Index
chemical_list: D008055:Lipids; D008565:Membrane Proteins; C419195:TM6SF2 protein, human