ArticlePLoS genetics2020
A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.
Erratum issuedOpen access · goldAbstract read
In one paragraph
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 103 papers, 4 of them syntheses that pooled it.
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103citing papers in PubMed, 4 pooled it
14.7field-weighted citation impact, top 1% of its field
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Who cites it
103 citing papers in PubMed, 4 syntheses or guidelines pooled it, 154 citations in OpenAlex.
- Convergent application of traditional Chinese medicine and gut microbiota in ameliorate of cirrhosis: a data mining and Mendelian randomization study.Frontiers in cellular and infection microbiology · 2023Pooled it
- Genome-Wide Association Study of NAFLD Using Electronic Health Records.Hepatology communications · 2022Pooled it
- Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease.Cell reports. Medicine · 2021Pooled it
- rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.Journal of hepatology · 2021Pooled it
- MASLD, diabetes and PMOS across the female life stages.Diabetologia · 2026Review
- Genetics of MASLD: a diabetes perspective.Diabetologia · 2026Review
- Prime editing models the MTARC1 A165T variant in human liver organoids, demonstrating reduced steatosis, inflammation, and fibrosis.Hepatology communications · 2026Article
- The CYB5R3-mARC1 Redox Axis in Metabolic Dysfunction-associated Steatotic Liver Disease: Mechanistic Basis and Therapeutic Prospects across the Steatosis-Cirrhosis-Hepatocellular Carcinoma Spectrum.Journal of clinical and translational hepatology · 2026Review
- Genetic and genomic insights across the steatotic liver disease spectrum.Clinical and molecular hepatology · 2026Review
- Divergence of the CYB5R3-mARC1 Redox Axis Across the Human MASLD-to-Hepatocellular-Carcinoma Continuum: An Exploratory Analysis of Liver-Biopsy and Tumor Cohorts.International journal of molecular sciences · 2026Article
- Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.Circulation research · 2026Review
- Integrative analyses elucidate transcriptional regulatory functions of risk alleles for metabolic liver disease.Nature genetics · 2026Article
- Integrating CRISPR genome editing with liver organoid and hiPSC-derived microfluidic platforms to model metabolic dysfunction-associated steatotic liver disease.Biochemistry and biophysics reports · 2026Review
- Proteomic Profiling of Plasma to Uncover Novel Intervention Targets and Prognostic Biomarkers for Chronic Liver Diseases.Diabetes, obesity & metabolism · 2026Article
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Association of Genetic Variants inInternational journal of molecular sciences · 2026Article
- MTARC1 p.A165 ablation reduces hepatocellular carcinoma aggressiveness in vitro and in vivo.Clinical and molecular hepatology · 2026Article
- Genetic modulators of metabolic dysfunction-associated steatotic liver disease (MASLD) and their epistatic interactions: from in vitro and animal models to clinical outcomes.BMC medical genomics · 2026Review
- Different types of sweetened coffee consumption, genetic predictor of gut microbe, and the risk of metabolic dysfunction-associated steatotic liver disease.Nutrition journal · 2026Article
- Sex- and mouse strain-related differences in body weight gain, composition of the gut microbiota, and levels of selected metabolites in response to a Western-style diet.BMC gastroenterology · 2026Article
43 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
42 authors at 16 institutions in 8 countries.
Connor A EmdinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.ORCID 0000-0003-2337-1229
Mary E HaasCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.ORCID 0000-0002-2816-9268
Amit V KheraCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.ORCID 0000-0001-6535-5839
Krishna AragamCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Mark ChaffinProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.ORCID 0000-0002-1234-5562
Derek KlarinProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.ORCID 0000-0002-4636-5780
George HindyProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Lan JiangDepartments of Biomedical Informatics, Vanderbilt University, Vanderbilt, Tennessee, United States of America.ORCID 0000-0002-2583-3661
Wei-Qi WeiDepartments of Biomedical Informatics, Vanderbilt University, Vanderbilt, Tennessee, United States of America.ORCID 0000-0003-4985-056X
Qiping FengDepartments of Medicine, Vanderbilt University, Vanderbilt, Tennessee, United States of America.ORCID 0000-0002-6213-793X
Juha KarjalainenProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Aki HavulinnaInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, FI, Helsinki, Finland.ORCID 0000-0002-4787-8959
Tuomo KiiskinenInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, FI, Helsinki, Finland.ORCID 0000-0002-6306-8227
Alexander BickProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.ORCID 0000-0001-5824-9595
Diego ArdissinoDivision of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.ORCID 0000-0003-0410-3528
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Heribert SchunkertDeutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany.ORCID 0000-0001-6428-3001
Ruth McPhersonUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada.ORCID 0000-0002-9087-6107
Hugh WatkinsDivision of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
Roberto ElosuaCardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain.
Matthew J BownDepartment of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom.
Nilesh J SamaniDepartment of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom.
Usman BaberThe Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Jeanette ErdmannInstitute for Cardiogenetics, University of Lübeck, Lübeck, Germany.ORCID 0000-0002-4486-6231
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
John DaneshCardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Danish SaleheenDepartment of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Kyong-Mi ChangPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0001-6811-9364
Marijana VujkovicPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0003-4924-5714
Ben VoightPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0002-6205-9994
Scott DamrauerPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0001-8009-1632
Julie LynchPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0003-0108-2127
David KaplanPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0002-3839-336X
Marina SerperPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0003-4899-2160
Philip TsaoVeterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.ORCID 0000-0001-7274-9318
Million Veteran Program
Josep MercaderCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.ORCID 0000-0001-8494-3660
Craig HanisHuman Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.ORCID 0000-0002-4880-5348
Mark DalyInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, FI, Helsinki, Finland.
Joshua DennyDepartments of Biomedical Informatics, Vanderbilt University, Vanderbilt, Tennessee, United States of America.ORCID 0000-0002-3049-7332
Stacey GabrielProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Sekar KathiresanDepartment of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
Broad Institute · USUniversity of Pennsylvania · USUniversity of Helsinki · FIVanderbilt University · USGerman Centre for Cardiovascular Research · DEUniversity of Leicester · GBCardiovascular Institute of the South · USCenter for Non-Communicable Diseases · PKCentre for Human Genetics · GBHarvard University · USJackson Memorial Hospital · USOspedale di Parma · ITUniversitat de Vic - Universitat Central de Catalunya · ESUniversity of Cambridge · GBUniversity of Ottawa · CAVA Palo Alto Health Care System · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MCenter for Common Disease GeneticsUM1HG008895 · NHGRI · BROAD INSTITUTE, INC. · PI DALY, MARK JOSEPH, GABRIEL, STACEY · 2016 to 2020
$111.2MTracking and Evaluation CoreU54GM115428 · NIGMS · UNIVERSITY OF MISSISSIPPI MED CTR · PI HALL, JOHN E · 2016 to 2025
$38.2MNorthwest Genomics CenterRC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2009 to 2009
$11.0MComprehensive Sequencing and Analysis of Variation in NHLBI CohortsRC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2009 to 2009
$10.2MUsing genetic variation to study biology of blood lipids & coronary heart diseaseR01HL127564 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Pradeep Natarajan, Gina Marie Peloso · 2015 to 2026
$7.3MAlgorithms to identify non-coding mutational burden and disease-relevant pathwaysR01DK101478 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI VOIGHT, BENJAMIN FRANKLIN · 2014 to 2018
$2.9MARRA - NHLBI Lung Cohorts Sequencing ProjectRC2HL102923 · NHLBI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, BARNES, KATHLEEN C · 2009 to 2009
$2.6MWHI Sequencing Project (WHISP)RC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2009 to 2009
$2.1MPolygenic prediction of common, complex diseasesK08HG010155 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI KHERA, AMIT VIKRAM · 2018 to 2021
$1.1MHuman Exome Sequencing in Six Well-Phenotyped NHLBI CohortsRC2HL103010 · NHLBI · UNIVERSITY OF VIRGINIA · PI RICH, STEPHEN S. · 2009 to 2009
$817kAlgorithms to identify non-coding mutational burden and disease-relevant pathwaysR56DK101478 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI VOIGHT, BENJAMIN FRANKLIN · 2019 to 2019
$272kBritish Heart Foundation CS/14/2/30841British Heart Foundation RG/18/10/33842British Heart Foundation RG2000010Department of Health IS_BRU_0211_20033NHGRI NIH HHS K08 HG010155NHGRI NIH HHS U54 HG003067NHGRI NIH HHS UM1 HG008895NHLBI NIH HHS HHSN268201300046CNHLBI NIH HHS HHSN268201300047CNHLBI NIH HHS HHSN268201300048CNHLBI NIH HHS HHSN268201300049CNHLBI NIH HHS HHSN268201300050CNHLBI NIH HHS R01 HL127564NHLBI NIH HHS RC2 HL102923NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS RC2 HL102925NHLBI NIH HHS RC2 HL102926NHLBI NIH HHS RC2 HL103010NIDDK NIH HHS R01 DK101478NIDDK NIH HHS R56 DK101478NIGMS NIH HHS U54 GM115428
Abstract
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.
Indexed as
Genetic Predisposition to DiseaseAllelesCholesterol, LDLCoronary Artery DiseaseDatasets as TopicFatty LiverFemaleHomozygoteHumansLiverLiver CirrhosisLiver Cirrhosis, AlcoholicLoss of Function MutationMaleMiddle AgedMitochondrial ProteinsCholesterol, LDLMitochondrial ProteinsMTARC1 protein, humanOxidoreductases
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