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

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posted on 2021-06-18, 10:36 authored by Connor A Emdin, Mary E Haas, Amit Khera, Krishna Aragam, Mark Chaffin, Derek Klarin, George Hindy, Lan Jiang, Wei-Qi Wei, Qiping Feng, Juha Karjalainen, Aki Havulinna, Tuomo Kiiskinen, Alexander Bick, Diego Ardissino, James G Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J Bown, Nilesh J Samani, Usman Baber, Jeanette Erdmann, Namrata Gupta, John Danesh, Danish Saleheen, Kyong-Mi Chang, Marijana Vujkovic, Ben Voight, Scott Damrauer, Julie Lynch, David Kaplan, Marina Serper, Philip Tsao, Josep Mercader, Craig Hanis, Mark Daly, Joshua Denny, Stacey Gabriel, Sekar Kathiresan
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 (lowfrequency 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.

Funding

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 CVgenes@target (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 M

History

Citation

Emdin CA, Haas ME, Khera AV, Aragam K, Chaffin M, Klarin D, et al. (2020) A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. PLoS Genet 16(4): e1008629. https://doi.org/10.1371/journal.pgen.1008629

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  • VoR (Version of Record)

Published in

PLoS Genetics

Volume

16

Issue

4

Pagination

e1008629

Publisher

Public Library of Science (PLoS)

issn

1553-7390

eissn

1553-7404

Acceptance date

2020-01-24

Copyright date

2020

Available date

2021-06-18

Spatial coverage

United States

Language

English

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