Transmembrane 6 Superfamily Member 2 Gene Variant Disentangles Nonalcoholic Steatohepatitis From Cardiovascular Disease

Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis may progress to fibrosis and may promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver due to reduced secretion of very low density lipoproteins. 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 nonalcoholic steatohepatitis. Liver damage was evaluated in 1201 patients who underwent liver biopsy for suspected nonalcoholic steatohepatitis; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1819 controls from the Swedish Obese Subjects 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 nonalcoholic steatohepatitis (OR 1.84, 95% 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 Swedish Obese Subjects cohort, E167K carriers had higher ALT and lower lipid levels (P<0.05), and a lower incidence of cardiovascular events (HR 0.61, 95% CI 0.39-0.95). Conclusions: Carriers of the TM6SF2 E167K variant are more susceptible to progressive nonalcoholic steatohepatitis, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export very low density lipoproteins is deleterious for the liver. (Hepatology 2014;).