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

By J. Kozlitina, E. Smagris, S. Stender, Børge G. Nordestgaard, Heather H. Zhou, A. Tybjærg-Hansen, T. Vogt, Helen H. Hobbs, Jonathan C. Cohen. Nature Genetics, 2014

1,133 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3920ca893695638ac6428c34d6a25bc3d0bad2e1

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Citations in the corpus

• Triglyceride metabolism in the liver (2017, neutral): “Finally, a polymorphism in Transmembrane 6 superfamily member 2 (TM6SF2) has been identified by human genome-wide association studies to be associated with hepatic steatosis (147, 236).”
• The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent (2016, positive): “Since alcoholic and nonalcoholic cirrhosis share the major common genetic risk determinants, namely the PNPLA3 I148M and TM6SF2 E167K variants 9, 10 , we tested the hypothesis that MBOAT7/TMC4 was associated with an increased risk of NAFLD and liver damage development.”
• Metabolism Disrupting Chemicals and Metabolic Disorders (2016, neutral): “located on chromosome 19 and associated with increased hepatic triglyceride content and lower serum lipoproteins [54, 55].”
• The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). (2016, background): “TM6SF2 protein promotes VLDL secretion, while the rs58542926 variant, through a loss of function, is associated with hepatic steatosis, lower plasma levels of VLDL and higher ALT levels [97].”