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Updated: Jun 4, 2025
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury
1Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Abstract:
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.
Insights
Identifying genetic factors for drug-induced liver injury (DILI) is crucial for patient safety. Research highlights human leucocyte antigen (HLA) alleles and other genes contributing to DILI risk, aiding in prediction and prevention.
Area of Science:
- Pharmacogenomics
- Hepatology
- Immunogenetics
Background:
- Idiosyncratic drug-induced liver injury (DILI) presents a significant clinical challenge.
- Identifying genetic risk factors for DILI is a long-standing priority for drug safety and patient management.
- Genome-wide association studies have advanced the identification of genetic predispositions to DILI.
Purpose of the Study:
- To review the progress in identifying genetic risk factors for drug-induced liver injury (DILI).
- To discuss the role of human leucocyte antigen (HLA) alleles and non-HLA genes in DILI.
- To explore the development and potential of polygenic risk scores for predicting DILI.
Main Methods:
- Review of genomic analysis, including genome-wide association studies (GWAS).
- Analysis of identified genetic risk factors for DILI associated with specific drugs (e.g., amoxicillin-clavulanate, flucloxacillin).
- Examination of the immunological mechanisms involving HLA alleles and T-cell responses, and the role of non-HLA genes in drug metabolism.
Main Results:
- Genetic risk factors for DILI have been identified for amoxicillin-clavulanate and flucloxacillin, with underlying mechanisms understood.
- Progress has been made in identifying genetic risk factors for DILI from anti-infectives, herbal remedies, and NSAIDs.
- Human leucocyte antigen (HLA) alleles are major genetic risk factors, presenting self-peptides to T cells; non-HLA genes also contribute.
- Polygenic risk scores have been developed to predict DILI, indicating the existence of non-HLA genetic risk factors.
Conclusions:
- Genetic factors, particularly specific HLA alleles, play a significant role in idiosyncratic drug-induced liver injury (DILI).
- Non-HLA genes also contribute to DILI susceptibility through T-cell modulation and drug metabolism.
- Polygenic risk scores show promise for predicting DILI, suggesting a complex genetic architecture beyond HLA associations.
