Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease

<jats:sec> <jats:title/> <jats:p>Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the <jats:italic toggle="yes">TM6SF2</jats:italic> 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 <jats:italic toggle="yes">TM6SF2</jats:italic> 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 <jats:italic toggle="yes">TM6SF2</jats:italic> 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 (<jats:italic toggle="yes">P</jats:italic> < 0.05), had more‐severe steatosis, necroinflammation, ballooning, and fibrosis (<jats:italic toggle="yes">P</jats:italic> < 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 <jats:italic toggle="yes">PNPLA3</jats:italic> 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 (<jats:italic toggle="yes">P</jats:italic> < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39‐0.95). <jats:italic toggle="yes">Conclusions</jats:italic>: Carriers of the <jats:italic toggle="yes">TM6SF2</jats:italic> E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver. (H<jats:sc>epatology</jats:sc> 2015;61:506‐514)</jats:p> </jats:sec>