title: The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors: Rosellina Margherita
authors: RM
authors: Mancina
authors: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors: Paola
authors: P
authors: Dongiovanni
authors: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors: Salvatore
authors: S
authors: Petta
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors: Piero
authors: P
authors: Pingitore
authors: Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy.
authors: Marica
authors: M
authors: Meroni
authors: Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy.
authors: Raffaela
authors: R
authors: Rametta
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors: Jan
authors: J
authors: Borén
authors: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
authors: Tiziana
authors: T
authors: Montalcini
authors: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
authors: Arturo
authors: A
authors: Pujia
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors: Olov
authors: O
authors: Wiklund
authors: Diabetes and Cardiovascular Disease-Genetic Epidemiology, Lund, Sweden.
authors: George
authors: G
authors: Hindy
authors: Division of Gastroenterology, Fondazione Tommaso Campanella, University Magna Graecia of Catanzaro, Italy.
authors: Rocco
authors: R
authors: Spagnuolo
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors: Benedetta Maria
authors: BM
authors: Motta
authors: Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy.
authors: Rosaria Maria
authors: RM
authors: Pipitone
authors: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors: Antonio
authors: A
authors: Craxì
authors: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantationm Università degli Studi di Milano, Milan, Italy.
authors: Silvia
authors: S
authors: Fargion
authors: Hepatometabolic Unit, Bambin Gesù Hospital, Rome, Italy.
authors: Valerio
authors: V
authors: Nobili
authors: Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Pirjo
authors: P
authors: Käkelä
authors: Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Vesa
authors: V
authors: Kärjä
authors: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Ville
authors: V
authors: Männistö
authors: Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland; Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors: Jussi
authors: J
authors: Pihlajamäki
authors: Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts.
authors: Dermot F
authors: DF
authors: Reilly
authors: Merck Research Laboratories, Diabetes Department, Kenilworth, New Jersey; Waters Corporation, Milford, Massachusetts.
authors: Jose
authors: J
authors: Castro-Perez
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Julia.Kozlitina@UTSouthwestern.edu.
authors: Julia
authors: J
authors: Kozlitina
authors: 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.
authors: Luca
authors: L
authors: Valenti
authors: 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.
authors: Stefano
authors: S
authors: Romeo
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010716:Phosphatidylinositols / Q000378:metabolism; D011110:Polymorphism, Genetic; D066244:Proton Magnetic Resonance Spectroscopy; D012307:Risk Factors; D012720:Severity of Illness Index; D013781:Texas / Q000453:epidemiology; D014280:Triglycerides / Q000378:metabolism; D044465:White People / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D010716:Phosphatidylinositols; C000616533:TMC4 protein, human; D014280:Triglycerides; D000217:Acyltransferases; C000616532:MBOAT7 protein, human; D000123:Acetyltransferases
keywords: Arachidonic Acid; NASH; PNPLA3; TM6SF2