title: Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes.
abstract: A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted ≥F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection.
  
  
  
  The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34-46).
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Eslam
authors.affiliation: Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Henry Lik Yuen
authors.initials: HL
authors.lastname: Chan
authors.affiliation: NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK.
authors.forename: William L
authors.initials: WL
authors.lastname: Irving
authors.affiliation: Kirby Institute, The University of New South Wales, Sydney, NSW, Australia.|St. Vincent's Hospital, Sydney, NSW, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Abate
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.affiliation: School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Leon A
authors.initials: LA
authors.lastname: Adams
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.|Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia.
authors.forename: Mustafa A M
authors.initials: MA
authors.lastname: Najim
authors.affiliation: Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Miele
authors.affiliation: Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.affiliation: Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Mollison
authors.affiliation: Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Riordan
authors.affiliation: Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gomez
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Rahme
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sheridan
authors.affiliation: Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.affiliation: Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: McLeod
authors.affiliation: The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Powell
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.|Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Douglas
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: David
authors.initials: D
authors.lastname: van der Poorten
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006525:Hepatitis, Viral, Human / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D019562:Viral Load / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C419195:TM6SF2 protein, human