An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity
- Hong-Hsing Liu1,7,8,
- Peng Lu1,7,
- Yingying Guo1,
- Erin Farrell1,
- Xun Zhang1,
- Ming Zheng2,
- Betty Bosano2,
- Zhaomei Zhang1,
- John Allard1,
- Guochun Liao1,
- Siyu Fu1,
- Jinzhi Chen1,
- Kimberly Dolim2,
- Ayako Kuroda2,
- Jonathan Usuka2,
- Janet Cheng1,
- William Tao2,
- Kevin Welch3,
- Yanzhou Liu4,
- Joseph Pease4,
- Steve A. de Keczer4,
- Mohammad Masjedizadeh4,
- Jing-Shan Hu1,
- Paul Weller2,
- Tim Garrow5 and
- Gary Peltz6
- 1Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California 94304, USA;
- 2Non-Clinical Safety, Roche Palo Alto, Palo Alto, California 94304, USA;
- 3Technical Sciences, Roche Palo Alto, Palo Alto, California 94304, USA;
- 4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda, Maryland 20892, USA;
- 5Department of Food Science and Nutrition, University of Illinois, Urbana, Illinois 61801, USA;
- 6Department of Anesthesia, Stanford University, Stanford, California 94305, USA
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↵7 These authors contributed equally to this work.
Abstract
Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.
Footnotes
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↵8 Corresponding author.
E-mail honghsing.liu{at}gmail.com; fax (650) 721-2420.
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[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE17649.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.097212.109.
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- Received June 12, 2009.
- Accepted September 24, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
