An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity

H. H Liu, P Lu, Y Guo, E Farrell, X Zhang, M Zheng, B Bosano, Z Zhang, J Allard, G Liao, S Fu, J Chen, K Dolim, A Kuroda, J Usuka, J Cheng, W Tao, K Welch, Y Liu, J Pease, S. A de Keczer, M Masjedizadeh, J. S Hu, P Weller, T Garrow and G. Peltz

Genome Research, 2010, 20(1), 28-35. DOI: 10.1101/gr.097212.109

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.

ASCI-ID: 1333-160