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The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
- Source :
-
Gastroenterology [Gastroenterology] 2016 May; Vol. 150 (5), pp. 1219-1230.e6. Date of Electronic Publication: 2016 Feb 02. - Publication Year :
- 2016
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Abstract
- 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.<br />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.<br />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.<br />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.<br /> (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Acetyltransferases metabolism
Acyltransferases metabolism
Biopsy
Case-Control Studies
Cross-Sectional Studies
Europe epidemiology
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Liver metabolism
Liver pathology
Liver Cirrhosis diagnosis
Liver Cirrhosis ethnology
Liver Cirrhosis metabolism
Male
Membrane Proteins metabolism
Non-alcoholic Fatty Liver Disease diagnosis
Non-alcoholic Fatty Liver Disease ethnology
Non-alcoholic Fatty Liver Disease metabolism
Phenotype
Phosphatidylinositols metabolism
Proton Magnetic Resonance Spectroscopy
Risk Factors
Severity of Illness Index
Texas epidemiology
Triglycerides metabolism
Acetyltransferases genetics
Acyltransferases genetics
Liver Cirrhosis genetics
Membrane Proteins genetics
Non-alcoholic Fatty Liver Disease genetics
Polymorphism, Genetic
White People genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 150
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 26850495
- Full Text :
- https://doi.org/10.1053/j.gastro.2016.01.032