Human Genetics

Expedited Pharmacogenomics

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Science  22 May 2009:
Vol. 324, Issue 5930, pp. 989
DOI: 10.1126/science.324_989b

Drug-induced liver injury is one of the most common reasons that approved drugs are recalled from the market and that clinical trials of experimental drugs are terminated early. Susceptibility to liver damage and other adverse drug reactions are in part genetically determined, and a major goal of pharmacogenomics research is to find genetic markers that can be used to identify at-risk individuals in advance of drug treatment. The search for such biomarkers in human populations has proven to be labor-intensive, but a new study suggests that the hunt can be streamlined by using data derived from genetically diverse mouse populations to guide the human studies.

Harrill et al. studied 36 inbred strains of mice given large doses of acetaminophen and found that there were large strain-dependent variations in drug-induced liver injury, as assessed by histology and by elevated serum levels of the liver enzyme alanine aminotransferase (ALT). Candidate genes likely to be responsible for the inter-strain differences were identified by whole-genome association analysis, and the human versions of these genes were then sequenced in two small groups of humans. Sequence variants in several of these candidate genes—which, interestingly, encode proteins related to immune function rather than to xenobiotic metabolism—were indeed found to corre-late with the presence of acetaminophen-induced elevation of serum ALT levels in the humans.

Genome Res. 19, 10.1101/gr.090241.108 (2009).

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