title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 × 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations (n > 80,000). When recombinant protein was expressed in cultured hepatocytes, 50% less Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2. Adeno-associated virus-mediated short hairpin RNA knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD.
authors: 1] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
authors: Julia
authors: J
authors: Kozlitina
authors: 1] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
authors: Eriks
authors: E
authors: Smagris
authors: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Stefan
authors: S
authors: Stender
authors: 1] Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Børge G
authors: BG
authors: Nordestgaard
authors: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors: Heather H
authors: HH
authors: Zhou
authors: 1] Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [2] Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Anne
authors: A
authors: Tybjærg-Hansen
authors: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors: Thomas F
authors: TF
authors: Vogt
authors: 1] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Helen H
authors: HH
authors: Hobbs
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Jonathan C
authors: JC
authors: Cohen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002853:Chromatography, Liquid; D000229:Dependovirus; D059472:Exome / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics*; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D022781:Hepatocytes; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D011994:Recombinant Proteins; C419195:TM6SF2 protein, human; D014280:Triglycerides; D000410:Alanine Transaminase