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

• Published in: Nature genetics Vol. 46; no. 4; pp. 352 - 356
• Main Authors: Kozlitina, Julia, Smagris, Eriks, Stender, Stefan, Nordestgaard, Børge G, Zhou, Heather H, Tybjærg-Hansen, Anne, Vogt, Thomas F, Hobbs, Helen H, Cohen, Jonathan C
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.04.2014
• Subjects: Adipose Tissue - metabolism; African Americans; Alanine Transaminase - blood; Amino Acid Sequence; Animals; Base Sequence; Cholesterol; Chromatography, Liquid; Dependovirus; Exome - genetics; Exome sequencing; Fatty liver; Fatty Liver - genetics; Gene Knockdown Techniques; Genealogy; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genetic research; Genetic susceptibility; Hepatocytes; Hispanic people; Humans; Hypotheses; Lipids; Lipoproteins; Lipoproteins, VLDL - secretion; Liver - metabolism; Membrane Proteins - genetics; Methods; Mice; Molecular Sequence Data; Mutation, Missense - genetics; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Sequence Alignment; Sequence Analysis, DNA; Studies; Triglycerides; Triglycerides - metabolism
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2901

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.