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

• DOI: 10.1038/ng.2901
• Publication Date: 2014-02-16T19:04:55Z
• Authors: Julia Kozlitina; Eriks Smagris; Stefan Stender; Børge G Nordestgaard; Heather H Zhou; Anne Tybjærg-Hansen; Thomas F Vogt; Helen H Hobbs; Jonathan C Cohen
• Keywords: Lipoproteins; Molecular Sequence Data; Mutation, Missense; Lipoproteins, VLDL; Real-Time Polymerase Chain Reaction; Article; Mice; 03 medical and health sciences; Non-alcoholic Fatty Liver Disease; Animals; Humans; Exome; Genetic Predisposition to Disease; Amino Acid Sequence; Triglycerides; Genetic Association Studies; Chromatography; Liquid; 0303 health sciences; Base Sequence; Membrane Proteins; Alanine Transaminase; DNA; Dependovirus; Recombinant Proteins; 3. Good health; Fatty Liver; Adipose Tissue; Liver; Gene Knockdown Techniques; Mutation; Hepatocytes; Missense; VLDL; Sequence Alignment; Sequence Analysis; Chromatography, Liquid

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.