<scp>TM</scp>6<scp>SF</scp>2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of <scp>PNPLA</scp>3 polymorphism

Coppola, Nicola; Zampino, R.; Cirillo, Grazia; Stanzione, Maria; Macera, Margherita; Boemio, Adriana; Grandone, Anna; Pisaturo, M.; Marrone, Aldo; Adinolfi, Luigi Elio; Sagnelli, E.; Giudice, Emanuele Miraglia del

doi:10.1111/liv.12781

Cited by 55 publications

(63 citation statements)

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“…The analysis included a total of 4187 subjects from which the values of ALT according to E167K genotypes could be extracted15161718; this sample included 3680 patients with HCV and 507 patients with HBV. Only two studies reported data on AST levels1516.…”

Section: Resultsmentioning

confidence: 99%

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Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

Sookoian

Pirola

2016

Sci Rep

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A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10−6, n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents –2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a –28% increase in serum ALT.

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Section: Resultsmentioning

confidence: 99%

“…Only two studies reported data on AST levels1516. The mean value of ALT and AST according to genotypes of the dominant model of rs58542926 in each study is disclosed in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

Sookoian

Pirola

2016

Sci Rep

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“…5, 9, 10, 17, 34–37 More recently, the same variant in the TM6SF2 gene has been identified as a novel risk locus for alcohol-related cirrhosis in the European descent and validated in two independent European cohorts. 38 The global Tm6sf2 KO mice and liver-specific transgenic mice allowed us to determine the long-term effect of TM6SF2 on lipid metabolism in the liver.…”

Section: Discussionmentioning

confidence: 96%

Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice

Fan

Guo

et al. 2016

Gastroenterology

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BACKGROUND & AIMS The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. METHODS C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets (HFD). Blood samples were collected from all mice and plasma levels of TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol, and triglycerides were measured. Liver tissues were collected and analyzed by histology, real-time PCR, and immunoblot assays. Adenovirus vectors were used to express transgenes in cultured Hep3B hepatocytes. RESULTS Liver-specific expression of TM6SF2 increased plasma levels of TC and LDL-c, compared with controls, and altered liver expression of genes that regulate cholesterol metabolism. Tm6sf2-knockout mice had decreased plasma levels of TC and LDL-c, compared with controls, and consistent changes expression of genes that regulate cholesterol metabolism. Expression of TM6SF2 promoted cholesterol biosynthesis in hepatocytes. CONCLUSIONS TM6SF2 regulates cholesterol metabolism in mice and might be a therapeutic target for cardiovascular disease.

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“…In fact, a recent study on chronic hepatitis C showed that while TM6SF2-E167K variant is an independent predictor of liver, no difference in necroinfl ammatory or fi brosis scores was found among carriers and noncarriers of the risk allele [ 51 ]. Finally, functional studies on TM6SF2 gene demonstrated that this locus and the mentioned variant are relevant on NAFLD disease biology.…”

Section: Gwas On Nafld and The Genetic Risk Of Disease Progressionmentioning

confidence: 95%

Genetic Basis of Alcoholic and Nonalcoholic Fatty Liver Disease

Sookoian

Pirola

2016

Alcoholic and Non-Alcoholic Fatty Liver Disease

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TM6SF2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of PNPLA3 polymorphism

Abstract: This is the first demonstration that TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C.

Cited by 55 publications

References 24 publications

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice

Genetic Basis of Alcoholic and Nonalcoholic Fatty Liver Disease

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