title: An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity.
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.
authors.affiliation: Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California 94304, USA. honghsing.liu@gmail.com
authors.forename: Hong-Hsing
authors.initials: HH
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.forename: Erin
authors.initials: E
authors.lastname: Farrell
authors.forename: Xun
authors.initials: X
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Betty
authors.initials: B
authors.lastname: Bosano
authors.forename: Zhaomei
authors.initials: Z
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Guochun
authors.initials: G
authors.lastname: Liao
authors.forename: Siyu
authors.initials: S
authors.lastname: Fu
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Chen
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dolim
authors.forename: Ayako
authors.initials: A
authors.lastname: Kuroda
authors.forename: Jonathan
authors.initials: J
authors.lastname: Usuka
authors.forename: Janet
authors.initials: J
authors.lastname: Cheng
authors.forename: William
authors.initials: W
authors.lastname: Tao
authors.forename: Kevin
authors.initials: K
authors.lastname: Welch
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Pease
authors.forename: Steve A
authors.initials: SA
authors.lastname: de Keczer
authors.forename: Mohammad
authors.initials: M
authors.lastname: Masjedizadeh
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Hu
authors.forename: Paul
authors.initials: P
authors.lastname: Weller
authors.forename: Tim
authors.initials: T
authors.lastname: Garrow
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D004032:Diet; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D014814:Vitamin U / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D014814:Vitamin U; D000082:Acetaminophen; D050940:Betaine-Homocysteine S-Methyltransferase