Kevin Teo1, Kushala W M Abeysekera2, Leon Adams3, Elmar Aigner4, Quentin M Anstee5, Jesus M Banales6, Rajarshi Banerjee7, Priyadarshi Basu8, Thomas Berg9, Pallav Bhatnagar10, Stephan Buch11, Ali Canbay12, Sonia Caprio13, Ankita Chatterjee8, Yii-Der Ida Chen14, Abhijit Chowdhury15, Ann K Daly16, Christian Datz17, Dana de Gracia Hahn1, Johanna K DiStefano18, Jiawen Dong1, Amedine Duret1, Connor Emdin19, Madison Fairey1, Glenn S Gerhard20, Xiuqing Guo14, Jochen Hampe11, Matthew Hickman2, Lena Heintz21, Christian Hudert22, Harriet Hunter1, Matt Kelly7, Julia Kozlitina23, Marcin Krawczyk24, Frank Lammert21, Claudia Langenberg25, Joel Lavine26, Lin Li27, Hong Kai Lim1, Rohit Loomba28, Panu K Luukkonen29, Phillip E Melton30, Trevor A Mori31, Nicholette D Palmer32, Constantinos A Parisinos33, Sreekumar G Pillai10, Faiza Qayyum34, Matthias C Reichert21, Stefano Romeo35, Jerome I Rotter14, Yu Ri Im1, Nicola Santoro36, Clemens Schafmayer37, Elizabeth K Speliotes38, Stefan Stender34, Felix Stickel39, Christopher D Still40, Pavel Strnad41, Kent D Taylor14, Anne Tybjærg-Hansen34, Giuseppina Rosaria Umano42, Mrudula Utukuri1, Luca Valenti43, Lynne E Wagenknecht44, Nicholas J Wareham25, Richard M Watanabe45, Julia Wattacheril46, Hanieh Yaghootkar47, Hannele Yki-Järvinen48, Kendra A Young49, Jake P Mann50. 1. School of Clinical Medicine, University of Cambridge, Cambridge, UK. 2. MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK. 3. Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, WA, Australia. 4. First Department of Medicine, Paracelsus Medical University Salzburg, Austria. 5. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 6. Department on Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain. 7. Perspectum Ltd, Oxford, UK. 8. National Institute of Biomedical Genomics, Kalyani, India. 9. Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. 10. Eli Lilly and Company, Indianapolis, IN, USA. 11. Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. 12. Gastroenterology, Hepatology and Infectiology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 13. Yale University, Department of Pediatrics, New Haven, CT, USA. 14. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA. 15. Institute of Post Graduate Medical Education and Research, Kolkata, India. 16. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. 17. Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria. 18. Diabetes and Fibrotic Disease Unit Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. 19. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, USA. 20. Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. 21. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. 22. Department of Pediatric Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 23. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. 24. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland. 25. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. 26. Department of Pediatrics, Columbia University, New York, NY, USA. 27. BioStat Solutions LLC, Frederick, MD, USA. 28. NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, CA, USA. 29. Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Yale University School of Medicine, New Haven, CT, USA. 30. School of Global Population Health, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia; School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia; Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, Australia. 31. Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia. 32. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. 33. Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK. 34. Department of Clinical Biochemistry, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 35. Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. 36. Yale University, Department of Pediatrics, New Haven, CT, USA; Department of Medicine and Health Sciences 'V. Tiberio' University of Molise, Campobasso, Italy. 37. Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany. 38. Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA. 39. Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. 40. Geisinger Obesity Institute, Danville, PA, USA. 41. Medical Clinic III, University Hospital RWTH Aachen, Aachen, Germany. 42. Yale University, Department of Pediatrics, New Haven, CT, USA; Department of the Woman, the Child, of General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy. 43. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy. 44. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. 45. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 46. Department of Medicine, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY, USA. 47. Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK. 48. Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 49. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA. 50. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. Electronic address: jm2032@cam.ac.uk.
Abstract
BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
Authors: Stephan Buch; Felix Stickel; Eric Trépo; Michael Way; Alexander Herrmann; Hans Dieter Nischalke; Mario Brosch; Jonas Rosendahl; Thomas Berg; Monika Ridinger; Marcella Rietschel; Andrew McQuillin; Josef Frank; Falk Kiefer; Stefan Schreiber; Wolfgang Lieb; Michael Soyka; Nasser Semmo; Elmar Aigner; Christian Datz; Renate Schmelz; Stefan Brückner; Sebastian Zeissig; Anna-Magdalena Stephan; Norbert Wodarz; Jacques Devière; Nicolas Clumeck; Christoph Sarrazin; Frank Lammert; Thierry Gustot; Pierre Deltenre; Henry Völzke; Markus M Lerch; Julia Mayerle; Florian Eyer; Clemens Schafmayer; Sven Cichon; Markus M Nöthen; Michael Nothnagel; David Ellinghaus; Klaus Huse; Andre Franke; Steffen Zopf; Claus Hellerbrand; Christophe Moreno; Denis Franchimont; Marsha Y Morgan; Jochen Hampe Journal: Nat Genet Date: 2015-10-19 Impact factor: 38.330
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