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 journalArticle

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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 - 2014

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Exome
VLDL Lipoproteins
Liver
Fats
Dependovirus
Alanine Transaminase
Recombinant Proteins
LDL Cholesterol
Small Interfering RNA
Alkaline Phosphatase
Liver Diseases
Hepatocytes
Triglycerides
Non-alcoholic Fatty Liver Disease
Wounds and Injuries
Population
Genes
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. / Kozlitina, Julia; Smagris, Eriks; Stender, Stefan; Nordestgaard, Børge G.; Zhou, Heather H.; Tybjærg-Hansen, Anne; Vogt, Thomas F.; Hobbs, Helen H.; Cohen, Jonathan C.

In: Nature Genetics, Vol. 46, No. 4, 2014, p. 352-356.

Research output: Contribution to journalArticle

Kozlitina, Julia ; Smagris, Eriks ; Stender, Stefan ; Nordestgaard, Børge G. ; Zhou, Heather H. ; Tybjærg-Hansen, Anne ; Vogt, Thomas F. ; Hobbs, Helen H. ; Cohen, Jonathan C. / Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. In: Nature Genetics. 2014 ; Vol. 46, No. 4. pp. 352-356.
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