TY - JOUR
T1 - The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent
AU - Pipitone, Rosaria Maria
AU - Craxi, Antonio
AU - Petta, Salvatore
AU - Nobili, Valerio
AU - Kozlitina, Julia
AU - Rametta, Raffaela
AU - Montalcini, Tiziana
AU - Pipitone, Rosaria Maria
AU - Käkelä, Pirjo
AU - Hindy, George
AU - Mancina, Rosellina Margherita
AU - Pujia, Arturo
AU - Spagnuolo, Rocco
AU - Pingitore, Piero
AU - Männistö, Ville
AU - Castro-Perez, Jose
AU - Reilly, Dermot F.
AU - Meroni, Marica
AU - Motta, Benedetta Maria
AU - Borén, Jan
AU - Romeo, Stefano
AU - Valenti, Luca
AU - Dongiovanni, Paola
AU - Kärjä, Vesa
AU - Pihlajamäki, Jussi
AU - Valenti, Luca
AU - Wiklund, Olov
AU - Fargion, Silvia
PY - 2016
Y1 - 2016
N2 - Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.
AB - Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.
KW - Arachidonic Acid; NASH; PNPLA3; TM6SF2; Acetyltransferases; Acyltransferases; Biopsy; Case-Control Studies; Cross-Sectional Studies; Europe; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Hum
KW - Genetic; Gastroenterology
KW - Arachidonic Acid; NASH; PNPLA3; TM6SF2; Acetyltransferases; Acyltransferases; Biopsy; Case-Control Studies; Cross-Sectional Studies; Europe; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Hum
KW - Genetic; Gastroenterology
UR - http://hdl.handle.net/10447/248008
UR - http://www.journals.elsevier.com/gastroenterology/
M3 - Article
VL - 150
SP - 1219-1230e6
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
ER -