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

Julia Kozlitina, Eriks Smagris, Stefan Stender, Børge G. Nordestgaard, Heather H. Zhou, Anne Tybjærg-Hansen, Thomas F. Vogt, Helen H. Hobbs, Jonathan C. Cohen

Research output: Contribution to journalArticlepeer-review

556 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)352-356
Number of pages5
JournalNature genetics
Volume46
Issue number4
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Genetics

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