Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns

Kim, Daniel S.; Jackson, Anne; Li, Yatong K.; Stringham, Heather M.; Kuusisto, Johanna; Kangas, Antti J.; Soininen, Pasi; Ala‐Korpela, Mika; Burant, Charles F.; Salomaa, Veikko; Boehnke, Michael; Laakso, Markku; Speliotes, Elizabeth K.

doi:10.1194/jlr.p076034

Cited by 52 publications

(50 citation statements)

References 44 publications

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“…Because the metabolites were highly cross‐correlated (Figure ), we performed hierarchical clustering and with metabolite clusters shown in Table . Consistent with our previous report, the cirrhosis promoting allele rs58542926‐T ( TM6SF2 ) associated with decreased concentration of very low‐density, intermediate‐ and high‐density lipoproteins . The cirrhosis promoting allele rs2892474‐T ( SERPINA1 ) also associated with decreased glycoproteins with several other suggestive associations.…”

Section: Resultssupporting

confidence: 89%

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Chen

et al. 2020

Liver International

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Background and Aims Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver‐related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. Methods We carried out a genome‐wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top‐associating loci for replication with cirrhosis in a hospital‐based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. Results Unbiased genome‐wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase‐to‐platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. Conclusions We identified eight loci that reproducibly associate with population‐based cirrhosis and define their diverse effects on human diseases and traits.

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Section: Resultssupporting

confidence: 89%

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Chen

et al. 2020

Liver International

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“…However, whether the magnitude of association of these genetic variants with progressive liver disease is concordant with an increase in risk predicted from their effect on hepatic fat accumulation has not been tested so far. Furthermore, whether genetically determined hepatic fat influences insulin resistance remains a controversial question .…”

Section: Introductionmentioning

confidence: 99%

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver

et al. 2017

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Background and AimsNonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance.MethodsWe performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at‐risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population‐based Dallas Heart Study (DHS).ResultsHepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long‐term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.ConclusionThese data suggest that long‐term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

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“…The TM6SF2 E167K missense mutation has been reported to reduce plasma APOB levels in human populations [35,36], at least in part, by decreasing its secretion [16]. TM6SF2 silencing also inhibits APOB secretion in two human hepatoma cell lines [12].…”

Section: Discussionmentioning

confidence: 99%

Disruption of the ERLIN–TM6SF2–APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease

Sun

et al. 2020

PLoS Genet

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Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.

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Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns

Cited by 52 publications

References 44 publications

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver

Disruption of the ERLIN–TM6SF2–APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease

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