Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications

Kaliyaperumal, Kalaiyarasi and Grove, Jane I. and Delahay, Robin M. and Griffiths, William. J.H. and Duckworth, Adam and Aithal, Guruprasad P. (2018) Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications. Journal of Hepatology . ISSN 1600-0641

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Abstract

A number of drug-specific and host-related factors contribute to the development of drug-induced liver injury (DILI). Investigations focused on genetic susceptibility to DILI have advanced our understanding of the pathogenesis of this rare, yet potentially life-threatening adverse reaction. Candidate gene studies involving well-characterized patients with DILI and drug-exposed controls have identified single nucleotide polymorphisms (SNPs) affecting the metabolism and clearance of specific drugs and hence, influencing individual’s susceptibility to DILI. On the other hand, a series of genome-wide association studies (GWASs) have revealed a number of Human Leucocyte Antigen (HLA) alleles that are associated with DILI secondary to compounds with dissimilar chemical structures, highlighting the role of adaptive immune responses in the development of liver damage. These risk alleles, such as HLA-DRB1*15:02 illustrated by the example presented in the clinical vignette, determine the physicochemical properties of the peptide-binding grooves of the HLA molecules and increase the likelihood of DILI in a susceptible individual by altering the nature or the magnitude of immune-mediated liver injury. Associations of HLA alleles with DILI secondary to specific drugs can be translated into genetic tests, and when performed selectively, can improve the accuracy of diagnosis of DILI as well as assist in identifying the correct causal agent when the event could be attributed to more than one drug.

Item Type: Article
RIS ID: https://nottingham-repository.worktribe.com/output/933467
Keywords: Drug-induced liver injury (DILI); Amoxicillin-clavulanic acid; HLA-DRB1*15:02; Major Histocompatibility Complex (MHC); Peptide-binding groove; diagnostic; genotyping
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Nottingham Digestive Diseases Centre
Identification Number: https://doi.org/10.1016/j.jhep.2018.05.013
Depositing User: Grove, Jane
Date Deposited: 08 May 2018 12:31
Last Modified: 04 May 2020 19:37
URI: http://eprints.nottingham.ac.uk/id/eprint/51566

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