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

TY - JOUR

T1 - Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

AU - Kozlitina, Julia

AU - Smagris, Eriks

AU - Stender, Stefan

AU - Nordestgaard, Børge G

AU - Zhou, Heather H

AU - Tybjærg-Hansen, Anne

AU - Vogt, Thomas F

AU - Hobbs, Helen H

AU - Cohen, Jonathan C

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

KW - Adipose Tissue

KW - Alanine Transaminase

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Chromatography, Liquid

KW - Dependovirus

KW - Exome

KW - Fatty Liver

KW - Gene Knockdown Techniques

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Hepatocytes

KW - Humans

KW - Lipoproteins, VLDL

KW - Liver

KW - Membrane Proteins

KW - Mice

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Non-alcoholic Fatty Liver Disease

KW - Real-Time Polymerase Chain Reaction

KW - Recombinant Proteins

KW - Sequence Alignment

KW - Sequence Analysis, DNA

KW - Triglycerides

U2 - 10.1038/ng.2901

DO - 10.1038/ng.2901

M3 - Journal article

C2 - 24531328

SN - 1061-4036

VL - 46

SP - 352

EP - 356

JO - Nature: New biology

JF - Nature: New biology

IS - 4

ER -