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

Kaliyaperumal, Kalaiyarasi; Grove, Jane I.; Delahay, Robin M.; Griffiths, William. J.H.; Duckworth, Adam; Aithal, Guruprasad P.

Authors

Kalaiyarasi Kaliyaperumal

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JANE GROVE jane.grove@nottingham.ac.uk
Assistant Professor

Robin M. Delahay

William. J.H. Griffiths

Adam Duckworth



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.

Citation

Kaliyaperumal, K., Grove, J. I., Delahay, R. M., Griffiths, W. J., Duckworth, A., & Aithal, G. P. (2018). Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications. Journal of Hepatology, 69(4), 948-957. https://doi.org/10.1016/j.jhep.2018.05.013

Journal Article Type Article
Acceptance Date May 2, 2018
Online Publication Date May 21, 2018
Publication Date 2018-10
Deposit Date May 8, 2018
Publicly Available Date May 22, 2019
Journal Journal of Hepatology
Print ISSN 0168-8278
Electronic ISSN 1600-0641
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 69
Issue 4
Pages 948-957
DOI https://doi.org/10.1016/j.jhep.2018.05.013
Keywords Drug-induced liver injury (DILI); Amoxicillin-clavulanic acid; HLA-DRB1*15:02; Major Histocompatibility Complex (MHC); Peptide-binding groove; diagnostic; genotyping
Public URL https://nottingham-repository.worktribe.com/output/933467
Publisher URL https://www.sciencedirect.com/science/article/pii/S0168827818320592

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Grand rounds DILI FINAL 020518 full manuscript.pdf (722 Kb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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