Meta-Analysis

. 2021 Jan;74(1):20-30.

doi: 10.1016/j.jhep.2020.08.027. Epub 2020 Aug 31.

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

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; EU-PNAFLD Investigators; Connor Emdin¹⁹, Madison Fairey¹, Glenn S Gerhard²⁰; GOLD Consortium; 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

Collaborators, Affiliations

Collaborators

Affiliations

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.

PMID: 32882372
PMCID: PMC7755037
DOI: 10.1016/j.jhep.2020.08.027

Meta-Analysis

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Kevin Teo et al. J Hepatol. 2021 Jan.

. 2021 Jan;74(1):20-30.

doi: 10.1016/j.jhep.2020.08.027. Epub 2020 Aug 31.

Authors

Collaborators

Affiliations

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.

PMID: 32882372
PMCID: PMC7755037
DOI: 10.1016/j.jhep.2020.08.027

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], p_z = 4.8×10^-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p_z = 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], p_z = 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 (p_z = 0.002) and lower serum triglycerides (p_z = 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.

Keywords: ALSPAC; Diabetes; Fibrosis; MBOAT7; NAFLD; Triglyceride.

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Conflict of interest statement

Conflict of interest C.E. reports receiving personal fees from Navitor Pharma and Novartis. The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

**Fig. 1**
The effect of rs641738C>T on liver fat. Data from 29,679916 individuals with CT, MRI or MRS liver fat. rs641738C>T was positively associated with liver fat in Caucasian populations (using an additive model of inheritance), where data represent SD change in normalised liver fat per T-allele. Meta-analysis was performed using random effects with DerSimonian-Laird method for estimation of tau². Additional references are available in the Supplementary Data. MRS, magnetic resonance spectroscopy; UKBB, UK BioBank.

**Fig. 2**
rs641738C>T is associated with higher odds of diagnosis of NAFLD. Data from 52,17333,263 adults (11,3019,713 cases and 40,87223,550 controls) with radiologically or histologically defined steatosis for presence vs. absence of NAFLD using a recessive model of inheritance (CC + CT *vs.* TT). Meta-analysis was performed using random effects with DerSimonian-Laird method for estimation of tau². Additional references are available in the Supplementary Data. LBC, Liver Biopsy Cohort; OR, odds ratio.

**Fig. 3**
The effect of rs641738C>T on the presence of advanced fibrosis in adult patients with NAFLD. Data from 7,6926,211 adults (1,214828 cases and 6,4785,383 controls) with biopsy-proven NAFLD comparing advanced fibrosis (F3–F4) vs. F0–F2, using a recessive model of inheritance (CC + CT *vs.* TT). Meta-analysis was performed using random effects with DerSimonian-Laird method for estimation of tau². Additional references are available in the Supplementary Data. LBC, Liver Biopsy Cohort; OR, odds ratio.

**Fig. 4**
rs641738C>T is associated with higher odds of NAFLD-HCC. Data from 2,328 adults with NAFLD assessing for the presence vs. absence of HCC, using a recessive model of inheritance (CC + CT *vs.* CT). Meta-analsysis was performed using random effects with DerSimonian-Laird method for estimation of tau².

**Fig. 5**
rs641738C>T is positively associated with ALT in Caucasian populations in GWAS. Meta-analysis using linear regression of GWAS summary statistics from 609,794 participants for the association between rs641738C>T and logarithmically transformed ALT. Meta-analysis was performed using random effects with DerSimonian-Laird method for estimation of tau². Additional references are available in the Supplementary Data. GWAS, genome-wide association studies; UKBB, UK BioBank.

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References

1. Speliotes E.K., Yerges-armstrong L.M., Wu J., Hernaez R., Kim L.J., Palmer C.D. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324. - PMC - PubMed
1. Romeo S., Sanyal A., Valenti L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 2020;31:35–45. - PubMed
1. Buch S., Stickel F., Trépo E., Way M., Herrmann A., Nischalke H.D. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015;47:1443–1448. - PubMed
1. Innes H., Buch S., Hutchinson S., Guha I.N., Morling J.R., Barnes E. Genome-wide association study for alcohol-related cirrhosis identifies risk loci in MARC1 and HNRNPUL1. Gastroenterology. 2020 doi: 10.1053/j.gastro.2020.06.014. In press. - DOI - PubMed
1. Mancina R.M., Dongiovanni P., Petta S., Pingitore P., Meroni M., Rametta R. The MBOAT7-TMC4 Variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150:1219–1230. - PMC - PubMed

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rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Collaborators

Affiliations

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

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