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. Epub 2014 Feb 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / metabolism*
  • Alanine Transaminase / blood
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromatography, Liquid
  • Dependovirus
  • Exome / genetics
  • Fatty Liver / genetics*
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Hepatocytes
  • Humans
  • Lipoproteins, VLDL / metabolism
  • Liver / metabolism*
  • Membrane Proteins / genetics*
  • Mice
  • Molecular Sequence Data
  • Mutation, Missense / genetics
  • Non-alcoholic Fatty Liver Disease
  • Real-Time Polymerase Chain Reaction
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Triglycerides / metabolism


  • Lipoproteins, VLDL
  • Membrane Proteins
  • Recombinant Proteins
  • TM6SF2 protein, human
  • Triglycerides
  • Alanine Transaminase