Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury

Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.