Rosellina Margherita Mancina1, Paola Dongiovanni2, Salvatore Petta3, Piero Pingitore1, Marica Meroni4, Raffaela Rametta4, Jan Borén1, Tiziana Montalcini5, Arturo Pujia5, Olov Wiklund6, George Hindy7, Rocco Spagnuolo8, Benedetta Maria Motta1, Rosaria Maria Pipitone4, Antonio Craxì3, Silvia Fargion9, Valerio Nobili10, Pirjo Käkelä11, Vesa Kärjä12, Ville Männistö13, Jussi Pihlajamäki14, Dermot F Reilly15, Jose Castro-Perez16, Julia Kozlitina17, Luca Valenti18, Stefano Romeo19. 1. Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden. 2. Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy. 3. Department of Gastroenterology, Università di Palermo, Palermo, Italy. 4. Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy. 5. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. 6. Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. 7. Diabetes and Cardiovascular Disease-Genetic Epidemiology, Lund, Sweden. 8. Division of Gastroenterology, Fondazione Tommaso Campanella, University Magna Graecia of Catanzaro, Italy. 9. Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy. 10. Hepatometabolic Unit, Bambin Gesù Hospital, Rome, Italy. 11. Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 12. Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 13. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 14. Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland; Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 15. Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts. 16. Merck Research Laboratories, Diabetes Department, Kenilworth, New Jersey; Waters Corporation, Milford, Massachusetts. 17. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Julia.Kozlitina@UTSouthwestern.edu. 18. Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy. Electronic address: luca.valenti@unimi.it. 19. Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: stefano.romeo@wlab.gu.se.
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. 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.
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 MBOAT7rs641738 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 MBOAT7rs641738 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.
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