Abstract
BackgroundDrug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood.MethodsTo study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView.ResultsWe demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity.ConclusionsOur bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI.
Highlights
Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing
Allele and haplotype frequencies are available at the Allele Frequency Net Database (AFND) website [33,34]. Major Histocompatibility Complex Database (dbMHC) database We extended our analyses to datasets available on the Major Histocompatibility Complex database [35], a public repository containing data previously submitted for the 13th International Histocompatibility Workshop for anthropological analysis [36]
We compared the frequencies of human leukocyte antigen (HLA) alleles associated with DILI in Caucasians from our cohort (n = 298) with the frequencies in other ethnic groups from AFND and dbMHC
Summary
Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Drug-induced T-cell mediated hypersensitivity reactions are feared by clinicians and pharmaceutical companies alike These reactions occur infrequently, they are still a cause of severe morbidity and mortality. The ‘pharmacological interaction with immune receptors’ (p-i) concept suggests that the interaction between drug, T-cell receptor and MHC molecule can be non-covalent and that direct stimulation of T cells can occur, independent of cellular processing [3] Both of these mechanisms highlight that the unique interaction between drug, T-cell receptor and MHC molecule is a key factor in the development of immunemediated adverse reactions to drugs and, as such, the study of HLA alleles represents a logical route to study the genetic basis of such immune-mediated reactions
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