Genetics of drug‐induced liver injury: Current knowledge and future prospects

Abstract

Idiosyncratic drug‐induced liver injury (DILI) remains an important clinical problem, both during drug development and the prescription of a range of licensed drugs. Although rare, the consequences are serious. Ongoing studies on genetic risk factors for DILI, especially genomewide association studies, have resulted in the identification of a number of genetic risk factors, including particular HLA alleles and a few non‐HLA genes, both immune‐related and metabolic. Some non‐HLA associations, such as N‐acetyltransferase 2 in isoniazid DILI and interferon regulatory factor 6 in interferon‐beta DILI are likely to be drug‐specific due to the role of the associated gene, but there is also evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs. Increased knowledge of genetic risk factors should assist in better understanding underlying DILI mechanisms and help improve methods for identifying hepatotoxic drugs early in development. HLA allele‐specific T cell proliferation together with in silico prediction of drug binding to specific HLA proteins have confirmed genetic findings for certain common causes of DILI. However, studies in hepatocytes exposed to high drug concentrations suggest toxicity that is not dependent on genotype also occurs. It seems likely that susceptibility to DILI involves several genetic risk factors combining with other factors that affect drug levels. Despite recent progress in detecting genetic risk factors for DILI, low positive predictive values mean that general implementation of genotyping prior to prescription of potentially hepatotoxic drugs is not useful currently.

Drug‐Induced Liver Injury with Commonly Used Antibiotics in the All of Us Research Program

“…DILI risk is determined by a complex interaction between clinical risk factors and the environment, 8 overlaid on each individual's unique genetic architecture 14,15 . Some antibiotics can cause DILI by creating covalent drug‐protein adducts that activate HLA‐dependent processes within the liver sinusoids, 10–12 and individual risk is therefore influenced by genetic variability in class I and class II HLA molecules 13–15 .…”

“…DILI risk is determined by a complex interaction between clinical risk factors and the environment, 8 overlaid on each individual's unique genetic architecture 14,15 . Some antibiotics can cause DILI by creating covalent drug‐protein adducts that activate HLA‐dependent processes within the liver sinusoids, 10–12 and individual risk is therefore influenced by genetic variability in class I and class II HLA molecules 13–15 . Variants in other immune‐specific genes have also been shown to influence this risk, 41,42 and currently there is great interest in quantifying the impact of these gene variants in the context of clinical risk factors using biobanks linked to dense longitudinal data 43,44 .…”

“…Some antibiotics (e.g., amoxicillin‐clavulanate) have the potential to cause liver injury by generating drug‐protein adducts that inadvertently activate the immune system 10–12 . Correspondingly, the risk for developing DILI can be influenced by genetic variability in class I and class II human leukocyte antigen (HLA) proteins 13–17 …”

Relevance of Pharmacogenomics to the Safe Use of Antimicrobials

“…As reviewed in detail elsewhere [ 5 ], there is evidence that many of these reactions are immune-mediated. There are also data pointing to genetic susceptibility to the reactions [ 6 ]. The most polymorphic immune-related genes in humans are the human leukocyte antigen (HLA) genes, which contribute to genetic susceptibility to a range of diseases where there is a genetic component.…”

“…The most polymorphic immune-related genes in humans are the human leukocyte antigen (HLA) genes, which contribute to genetic susceptibility to a range of diseases where there is a genetic component. The possibility that a HLA genotype contributes to the risk of idiosyncratic adverse drug reactions has therefore been investigated in detail and a number of specific HLA gene associations involving antimicrobial agents have been reported ( Table 1 ) [ 6 ]. Other immune-related genes may also contribute to this risk (see Section 5 below), but, to date, the strongest associations reported have been for the HLA genes.…”