1. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
- Author
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Kozlitina, Julia, Smagris, Eriks, Stender, Stefan, Nordestgaard, Børge G, Zhou, Heather H, Tybjærg-Hansen, Anne, Vogt, Thomas F, Hobbs, Helen H, and Cohen, Jonathan C
- Subjects
FATTY liver ,MOLECULAR biology ,ALANINE aminotransferase ,VERY low-density lipoproteins ,TRIGLYCERIDES ,ALKALINE phosphatase - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2014
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