Variant "TM6SF2:c.499G>A(p.Glu167Lys)"
Search results: 4 records
Variant information
Gene:
TM6SF2 
Variant:
TM6SF2:c.499G>A(p.Glu167Lys) 
Genomic location:
chr19:19379549(hg19) 
HGVS:
SO Term RefSeq
protein_coding NM_001001524.2:c.499G>A(p.Glu167Lys)
Alias:
TM6SF2:E167K 
dbSNP ID:
rs58542926  
GWAS trait:
total cholesterol measurement,triglyceride measurement,low density lipoprotein cholesterol measurement 
Modifier statisitcs
Record:
4 
Disorder:
2 
Reference:
3 
Effect type:
Expressivity(4)  
Modifier effect:
Altered serum lipid levels and altered severity(2) ,Altered circulating levels of alanine transaminase(1) ,Altered severity(1)  
Details：
  • Target disease:
    Abnormality Of The Cardiovascular System (HP:0001626)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered serum lipid levels and altered severity 
    Evidence:
    P<0.05 
    Effect:
    Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease.
    Alias in reference:
    TM6SF2:E167K
    Reference:
    PMID25251399
    Title:
    Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.
    Species studied:
    Human
    Abstract:
    Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95).
  • Target disease:
    Nonalcoholic Fatty Liver Disease (DOID_0080208)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered circulating levels of alanine transaminase 
    Evidence:
    P<0.05 
    Effect:
    The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase and is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD
    Alias in reference:
    TM6SF2:c.499G>A(p.Glu167Lys)
    Reference:
    PMID24531328
    Title:
    Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
    Species studied:
    Human
    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.
  • Target disease:
    Nonalcoholic Fatty Liver Disease (DOID_0080208)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered severity 
    Evidence:
    From review article 
    Effect:
    The polymorphism is a powerful modifier in the development of Nonalcoholic fatty liver disease
    Alias in reference:
    TM6SF2:E167K
    Reference:
    PMID26807382
    Title:
    TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease.
    Species studied:
    Human
    Abstract:
    Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver dysfunction worldwide, and its prevalence is highly associated with genetic susceptibility. The transmembrane 6 superfamily member 2 (TM6SF2) E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation, and its presence appears to be directly involved in the pathogenesis and development of NAFLD. Although this variant appears to be a novel powerful modifier in the development of NAFLD, whether it is associated with an increased risk of NAFLD-related liver fibrosis and hepatocellular carcinoma (HCC) remains to be determined. The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD, with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD. Additionally, the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.
  • Target disease:
    Nonalcoholic Fatty Liver Disease (DOID_0080208)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered serum lipid levels and altered severity 
    Evidence:
    P<0.05 
    Effect:
    Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease.
    Alias in reference:
    TM6SF2:E167K
    Reference:
    PMID25251399
    Title:
    Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.
    Species studied:
    Human
    Abstract:
    Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95).