Investigating the Role of Genetic Variants in Drug- Induced Liver Injury

Abstract

During drug research and the prescription of several licensed medications, drug-induced liver damage (DILI) continues to be a significant clinical issue. Despite being uncommon, there are grave repercussions. Numerous genetic risk factors, including specific HLA alleles and a few non-HLA genes that are immune-related and metabolic, have been identified as a result of ongoing research on genetic risk factors for DILI, particularly genomewide association studies. There is evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs, but some non-HLA associations, like 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. Enhanced comprehension of genetic risk factors ought to facilitate a deeper comprehension of the fundamental mechanisms behind DILI and enhance techniques for identifying hepatotoxic medications at an early stage of development. Genetic findings for several prevalent causes of DILI have been verified by HLA allele-specific T cell proliferation and in silico drug binding prediction to specific HLA proteins. Nonetheless, research conducted on hepatocytes exposed to elevated drug concentrations indicates the possibility of damage that is independent of genotype. It appears likely that a combination of genetic risk factors and other factors influencing medication levels contribute to susceptibility to DILI. Although there has been advancement in identifying genetic risk factors for DILI, limited positive predictive values indicate that genotyping patients before prescribing potentially hepatotoxic medications is not now helpful.