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Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease
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Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease
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Journal Article
Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease
2014
Overview
Helen Hobbs, Jonathan Cohen and colleagues identify a nonsynonymous variant in
TM6SF2
associated with susceptibility to nonalcoholic fatty acid liver disease. They further show that knockdown of
Tm6sf2
in mice results in increased liver triglyceride content and reduced very-low-density lipoprotein (VLDL) secretion, suggesting that impaired TM6SF2 function contributes causally to disease risk.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 45
/ 45/61
/ Alanine Transaminase - blood
/ Animal Genetics and Genomics
/ Animals
/ Genetic Predisposition to Disease - genetics
/ Humans
/ letter
/ Lipids
/ Lipoproteins, VLDL - secretion
/ Liver
/ Membrane Proteins - genetics
/ Methods
/ Mice
/ Mutation, Missense - genetics
/ Non-alcoholic Fatty Liver Disease
/ Real-Time Polymerase Chain Reaction
/ Recombinant Proteins - genetics
/ Recombinant Proteins - metabolism
/ Rodents
/ Studies
