Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Nature Genetics |
Volume | 46 |
Issue number | 4 |
Pages (from-to) | 352-356 |
Number of pages | 5 |
ISSN | 1061-4036 |
DOIs | |
Publication status | Published - Apr 2014 |
- Adipose Tissue, Alanine Transaminase, Amino Acid Sequence, Animals, Base Sequence, Chromatography, Liquid, Dependovirus, Exome, Fatty Liver, Gene Knockdown Techniques, Genetic Association Studies, Genetic Predisposition to Disease, Hepatocytes, Humans, Lipoproteins, VLDL, Liver, Membrane Proteins, Mice, Molecular Sequence Data, Mutation, Missense, Non-alcoholic Fatty Liver Disease, Real-Time Polymerase Chain Reaction, Recombinant Proteins, Sequence Alignment, Sequence Analysis, DNA, Triglycerides
Research areas
ID: 137666490