title: Genetic association studies in drug-induced liver injury.
abstract: A large number of case-control association studies on genetic susceptibility to drug-induced liver injury, involving both candidate gene and genome-wide association approaches, have now been reported. The strongest associations have been observed for human leukocyte antigen (HLA) class I and II genes and N-acetyltransferase 2 (NAT2). The associations with HLA class I and II genes are drug specific, though some apparently unrelated compounds show genetic associations with the same alleles. The underlying mechanism for the HLA association is likely to involve T-cell responses to either drug-protein adducts or to drug alone, but needs further investigation. The NAT2 association relates to liver injury induced by isoniazid, with most published studies finding an increased risk of injury in slow acetylators lacking NAT2 enzyme activity, presumably because of the accumulation of toxic metabolites. Other associations with genes relevant to drug disposition, innate immunity, oxidative stress, and mitochondrial function have also been reported, though these still need to be confirmed by replication in independent cohorts.
authors.affiliation: Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom. a.k.daly@ncl.ac.uk
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007538:Isoniazid / Q000009:adverse effects; D018384:Oxidative Stress / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D000995:Antitubercular Agents; D006680:HLA Antigens; D004364:Pharmaceutical Preparations; D007538:Isoniazid