TY - JOUR
T1 - Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease
AU - Dongiovanni, Paola
AU - Petta, Salvatore
AU - Maglio, Cristina
AU - Fracanzani, Anna Ludovica
AU - Pipitone, Rosaria
AU - Mozzi, Enrico
AU - Motta, Benedetta Maria
AU - Kaminska, Dorota
AU - Rametta, Raffaela
AU - Grimaudo, Stefania
AU - Pelusi, Serena
AU - Montalcini, Tiziana
AU - Alisi, Anna
AU - Maggioni, Marco
AU - Kärjä, Vesa
AU - Borén, Jan
AU - Käkelä, Pirjo
AU - Di Marco, Vito
AU - Xing, Chao
AU - Nobili, Valerio
AU - Dallapiccola, Bruno
AU - Craxi, Antonio
AU - Pihlajamäki, Jussi
AU - Fargion, Silvia
AU - Sjöström, Lars
AU - Carlsson, Lena M.
AU - Romeo, Stefano
AU - Valenti, Luca
N1 - Publisher Copyright:
© 2014 by the American Association for the Study of Liver Diseases.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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). Conclusions: Carriers of the TM6SF2 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.
AB - 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). Conclusions: Carriers of the TM6SF2 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.
UR - http://www.scopus.com/inward/record.url?scp=84921487729&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921487729&partnerID=8YFLogxK
U2 - 10.1002/hep.27490
DO - 10.1002/hep.27490
M3 - Article
C2 - 25251399
AN - SCOPUS:84921487729
SN - 0270-9139
VL - 61
SP - 506
EP - 514
JO - Hepatology
JF - Hepatology
IS - 2
ER -