A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease

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...

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Detalhes bibliográficos
Autores: Emdin, Connor A., Elosua Llanos, Roberto, Kathiresan, Sekar
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Universitat Pompeu Fabra
Repositório:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/47380
Acesso em linha:http://hdl.handle.net/10230/47380
http://dx.doi.org/10.1371/journal.pgen.1008629
Access Level:Acceso aberto
Palavra-chave:Cirrosi hepàtica
Fetge -- Malalties
Colesterol
Proteïnes
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dc.title.none.fl_str_mv A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
title A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
spellingShingle A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
Emdin, Connor A.
Cirrosi hepàtica
Fetge -- Malalties
Colesterol
Proteïnes
title_short A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
title_full A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
title_fullStr A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
title_full_unstemmed A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
title_sort A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease
dc.creator.none.fl_str_mv Emdin, Connor A.
Elosua Llanos, Roberto
Kathiresan, Sekar
author Emdin, Connor A.
author_facet Emdin, Connor A.
Elosua Llanos, Roberto
Kathiresan, Sekar
author_role author
author2 Elosua Llanos, Roberto
Kathiresan, Sekar
author2_role author
author
dc.subject.none.fl_str_mv Cirrosi hepàtica
Fetge -- Malalties
Colesterol
Proteïnes
topic Cirrosi hepàtica
Fetge -- Malalties
Colesterol
Proteïnes
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/47380
http://dx.doi.org/10.1371/journal.pgen.1008629
url http://hdl.handle.net/10230/47380
http://dx.doi.org/10.1371/journal.pgen.1008629
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/FP7/261123
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
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repository.name.fl_str_mv
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spelling A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver diseaseEmdin, Connor A.Elosua Llanos, RobertoKathiresan, SekarCirrosi hepàticaFetge -- MalaltiesColesterolProteïnesAnalyzing 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.This research has been conducted using the UK Biobank resource, application 7089. This work was funded by the National Institutes of Health (R01 HL127564 to S.K.). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). NJS is supported by the British Heart Foundation and is a NIHR Senior Investigator. The Munich MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project tegrat@senegVC (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02).This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence “Inflammation at Interfaces” and SFB 1123. The Italian Atherosclerosis, Thrombosis, and Vascular Biology (ATVB) Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Universita? 2010-2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. Funding for the exome-sequencing project (ESP) was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Exome sequencing in ATVB, PROCARDIS, Ottawa, PROMIS, Southern German Myocardial Infarction Study, and the Jackson Heart Study was supported by 5U54HG003067 (to Dr. Gabriel). Dr. Khera is supported by an institutional grant from the Broad Institute of MIT and Harvard (BroadIgnite), award numbers 1K08HG010155 and 5UM1HG008895 from the National Human Genome Research Institute, a Hassenfeld Scholar Award from Massachusetts General Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Public Library of Science (PLoS)202120212020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/47380http://dx.doi.org/10.1371/journal.pgen.1008629reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/EC/FP7/261123Copyright © 2020 Emdin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/473802026-06-12T07:21:37Z
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