Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease
Open accessAbstract
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.
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The mechanism linking the liver/lipid pPS to lower triglyceride levels may be deregulated triglyceride processing in the liver leading to a liver-mediated form of insulin resistance.
“this underlying mechanism may be due to deregulated triglyceride processing in the liver leading to a liver-mediated form of insulin resistance (24,30,31)”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [24]
The paper’s main text (indexed as Abstract; page unavailable) links increased liver triglycerides and lower plasma triglycerides to impaired VLDL secretion, supporting the liver-processing part of the proposed mechanism. It does not establish that this leads to liver-mediated insulin resistance; instead, it reports that the TM6SF2 variant was not associated with HOMA-IR. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe alleles at the liver/lipid cluster loci that increase T2D risk are associated with reduced serum triglyceride levels.
“The alleles at these loci that increase T2D risk are interestingly associated with reduced serum triglyceride levels”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [24]
The paper’s Abstract reports that the TM6SF2 Glu167Lys variant is associated with lower plasma triglyceride levels in three cohorts. It does not establish that this variant increases T2D risk or that T2D-risk alleles across the liver/lipid cluster loci have lower triglyceride levels. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which functional experiments have shown to relate to liver lipid metabolism.
“The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which have been shown through functional experiments to relate to liver lipid metabolism (24–31).”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [24]
The TM6SF2 rs58542926 minor allele is reportedly associated with MASLD and sometimes MASH.
“The rs58542926 minor allele of transmembrane 6 superfamily member 2 (TM6SF2) is also reportedly associated with MASLD and sometimes MASH (134, 140-142).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [142]
The HSD17B13 splice variant rs72613567 is protective against MASH, and HSD17B13 may contribute to MASH fibrosis by promoting pyrimidine catabolism.
“Furthermore, the splice variant rs72613567 in the Hydroxysteroid 17-beta Dehydrogenase 13 (HSD17B13) gene has been identified as protective against MASH, with HSD17B13 potentially contributing to MASH fibrosis by promoting pyrimidine catabolism (134, 140-142).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [142]
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- Authors
- Kozlitina, J., Smagris, E., Stender, S., Nordestgaard, B. G., Zhou, H. H., Tybjærg-Hansen, A., Vogt, T. F., Hobbs, H. H., & Cohen, J. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Copenhagen (DK)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hobbs, Helen H
- Cohen, Jonathan C
- ORCID
- Venue
- Nature Genetics
- Published
- 2014-02-16
- Volume
- 46
- Issue
- 4
- Pages
- 352-356
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3969786
- OpenAlex
- W1966549856
- Cited by
- 1,234
- References
- 22
- Citations by year
- 2026: 89 · 2025: 80 · 2024: 97 · 2023: 111 · 2022: 124 · 2021: 124 · 2020: 150 · 2019: 106 · 2018: 90 · 2017: 81 · 2016: 81 · 2015: 70 · 2014: 24 · 2013: 1
- FWCI
- 64.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001105)
- National Heart, Lung, and Blood Institute (HL-20948, 1HL092550, P01HL020948, RL1HL092550)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK090066, R01DK090066)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- non-alcoholic fatty liver disease, TM6SF2, PNPLA3, liver fat, VLDL secretion, hepatic triglycerides, LDL cholesterol, alanine aminotransferase, genetic susceptibility
- MeSH terms
- Dependovirus, Adipose Tissue, Alanine Transaminase, Amino Acid Sequence, Animals, Base Sequence, Chromatography, Liquid, Fatty Liver, Humans, Lipoproteins, VLDL, Liver, Membrane Proteins, Molecular Sequence Data, Recombinant Proteins, Triglycerides, Sequence Alignment, Sequence Analysis, DNA, Genetic Predisposition to Disease, Mutation, Missense, Hepatocytes, Mice, Gene Knockdown Techniques, Genetic Association Studies, Exome, Real-Time Polymerase Chain Reaction, Non-alcoholic Fatty Liver Disease
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