A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Autoři: Connor A. Emdin aff001;  Mary E. Haas aff001;  Amit V. Khera aff001;  Krishna Aragam aff001;  Mark Chaffin aff003;  Derek Klarin aff003;  George Hindy aff003;  Lan Jiang aff004;  Wei-Qi Wei aff004;  Qiping Feng aff005;  Juha Karjalainen aff003;  Aki Havulinna aff006;  Tuomo Kiiskinen aff006;  Alexander Bick aff003;  Diego Ardissino aff007;  James G. Wilson aff009;  Heribert Schunkert aff010;  Ruth McPherson aff011;  Hugh Watkins aff012;  Roberto Elosua aff014;  Matthew J. Bown aff017;  Nilesh J. Samani aff017;  Usman Baber aff018;  Jeanette Erdmann aff019;  Namrata Gupta aff003;  John Danesh aff021;  Danish Saleheen aff024;  Kyong-Mi Chang aff026;  Marijana Vujkovic aff026;  Ben Voight aff026;  Scott Damrauer aff026;  Julie Lynch aff026;  David Kaplan aff026;  Marina Serper aff026;  Philip Tsao aff027;  ;  Josep Mercader aff001;  Craig Hanis aff028;  Mark Daly aff006;  Joshua Denny aff004;  Stacey Gabriel aff003;  Sekar Kathiresan aff002
Působiště autorů: Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff001;  Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America aff002;  Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America aff003;  Departments of Biomedical Informatics, Vanderbilt University, Vanderbilt, Tennessee, United States of America aff004;  Departments of Medicine, Vanderbilt University, Vanderbilt, Tennessee, United States of America aff005;  Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI, Helsinki, Finland aff006;  Division of Cardiology, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy aff007;  Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy aff008;  Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America aff009;  Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany aff010;  University of Ottawa Heart Institute, Ottawa, Ontario, Canada aff011;  Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom aff012;  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom aff013;  Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain aff014;  CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain aff015;  Facultat de Medicina, Universitat de Vic-Central de Cataluña, Vic, Spain aff016;  Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom aff017;  The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff018;  Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany aff019;  DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany aff020;  Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom aff021;  Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom aff022;  National Institute of Health Research Blood and Transplant; Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom aff023;  Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff024;  Center for Non-Communicable Diseases, Karachi, Pakistan aff025;  Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff026;  Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America aff027;  Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America aff028;  Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff029;  Verve Therapeutics, Boston, Massachusetts, United States of America aff030
Vyšlo v časopise: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008629
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008629


Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

Klíčová slova:

Alcoholics – Alleles – Cirrhosis – Consortia – Coronary heart disease – Fatty liver – Cholesterol – Liver diseases


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