2. Academic Validation
  3. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

  • Nat Genet. 2014 Apr;46(4):352-6. doi: 10.1038/ng.2901.
Julia Kozlitina 1,  Eriks Smagris 1,  Stefan Stender 2,  Børge G Nordestgaard 3,  Heather H Zhou 4,  Anne Tybjærg-Hansen 5,  Thomas F Vogt 4,  Helen H Hobbs 6,  Jonathan C Cohen 7
Affiliations

Affiliations

  • 1 1] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
  • 2 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 3 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.
  • 4 Merck Research Laboratories, Kenilworth, New Jersey, USA.
  • 5 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.
  • 6 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.
  • 7 McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
PMID: 24531328 DOI: 10.1038/ng.2901
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.

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