Genome-Wide Association Studies in Drug-Induced Liver Injury: Step Change in Understanding the Pathogenesis

Hepatotoxicity constrains drug development and accounts for a substantial burden on health services. Genome-wide association studies (GWASs) have investigated potential genetic factors that explain interindividual variations in response tomedications leading to drug-induced liver injury (DILI). Although the proportion of GWASs investigating DILI is very small, those that have focused on this area have identified risk alleles with substantially higher risk ratios for susceptibility to DILI when compared with GWASs involving themajority of other complex diseases. Moreover, a relatively small number of human leukocyte antigen alleles are associated with DILI secondary to a range of medications. Because the encoded major histocompatibility complex proteins mediate antigen presentation to T cells, this provides evidence for a crucial central role for the adaptive immune system in DILI. Findings of GWASs should be considered during preclinical development of certain drugs. Genotyping may also have clinical applications, although it is currently limited to particular scenarios in relation to specific drugs.