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TM6SF2 – Gene, Variants & Liver Disease

TM6SF2 is a gene that plays a key role in hepatic lipid metabolism. Variants of this gene are linked to non-alcoholic fatty liver disease, liver cirrhosis, and cardiovascular conditions.

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Things worth knowing about "TM6SF2"

TM6SF2 is a gene that plays a key role in hepatic lipid metabolism. Variants of this gene are linked to non-alcoholic fatty liver disease, liver cirrhosis, and cardiovascular conditions.

What is TM6SF2?

TM6SF2 (Transmembrane 6 Superfamily Member 2) is a gene that encodes a transmembrane protein expressed predominantly in the liver and small intestine. The protein encoded by this gene is involved in the secretion of Very Low Density Lipoproteins (VLDL), thereby significantly influencing the body's lipid metabolism. Genetic variants in the TM6SF2 gene – in particular the variant E167K (rs58542926) – are among the most well-studied genetic risk factors for liver disease.

Function of the TM6SF2 Protein

The TM6SF2 protein is located in the endoplasmic reticulum and Golgi apparatus of liver cells. It plays a central role in the assembly and secretion of lipid-containing particles, especially VLDL particles, which transport triglycerides from the liver into the bloodstream. A reduced-function TM6SF2 protein leads to less triglyceride being exported from the liver, resulting in an accumulation of fat within liver cells, known as steatosis.

Genetic Variants and Their Significance

The E167K Variant

The best-known and most clinically relevant variant in the TM6SF2 gene is the single nucleotide polymorphism rs58542926, in which glutamic acid (E) at position 167 of the amino acid sequence is replaced by lysine (K). This substitution leads to reduced protein stability and function.

Carriers of the E167K variant have an increased risk of developing non-alcoholic fatty liver disease (NAFLD)
The risk of non-alcoholic steatohepatitis (NASH), as well as liver fibrosis and cirrhosis, is also elevated
The variant is associated with lower blood triglyceride and LDL cholesterol levels, as less fat is exported from the liver
At the same time, carriers have a reduced risk of heart attack and cardiovascular disease

Interaction with Other Genetic Factors

TM6SF2 variants interact with other known genetic risk factors for liver disease, particularly variants in the PNPLA3 gene (I148M) and the MBOAT7 gene. The co-occurrence of multiple risk variants can additively increase the overall risk of liver disease.

Associated Conditions

Non-Alcoholic Fatty Liver Disease (NAFLD/MASLD)

The TM6SF2 E167K variant is one of the strongest known genetic risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD. Affected individuals more frequently develop hepatic steatosis, which, without consistent lifestyle changes, can progress to inflammation (NASH), fibrosis, and ultimately cirrhosis.

Liver Cancer (Hepatocellular Carcinoma)

Studies indicate that carriers of the TM6SF2 risk variant also have a higher risk of developing hepatocellular carcinoma (HCC), especially in the presence of existing liver cirrhosis.

Cardiovascular Disease

Interestingly, carriers of the E167K variant are partially protected from certain cardiovascular diseases due to their lower blood lipid levels. However, this protective effect comes at the cost of an increased risk of liver disease.

Diagnosis and Genetic Testing

The TM6SF2 variant can be detected through genotyping or as part of comprehensive liver disease gene panels. Genetic testing may be particularly useful in patients with unexplained fatty liver disease, a family history of liver conditions, or elevated liver enzymes without an obvious cause. Testing is typically performed on a blood sample.

Therapeutic Implications

Currently, there is no specific therapy targeting TM6SF2. Management focuses on reducing the risk factors that promote the progression of liver disease:

Weight loss through dietary changes and physical activity
Treatment of associated conditions such as type 2 diabetes mellitus, obesity, and dyslipidaemia
Avoidance of alcohol and hepatotoxic substances
Regular medical monitoring of liver enzymes and imaging studies
TM6SF2 is also being investigated as a potential therapeutic target for future pharmacological treatments of MASLD

References

Kozlitina J et al. - Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics, 2014; 46(4): 352-356.
European Association for the Study of the Liver (EASL) - EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis. Journal of Hepatology, 2021; 75(3): 659-689.
Eslam M et al. - A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology, 2020; 73(1): 202-209.

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