In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers

To 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.We 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.Our 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.Drug-induced T-cell mediated hypersensitivity reactions are feared by clinicians and pharmaceutical companies alike. Although these reactions occur infrequently, they are still a cause of severe morbidity and mortality. They are difficult to predict during drug discovery because of a lack of in vitro or animal models and, because they occur at such a low frequency, they are often only detected during the late stages of drug development or, more commonly, during post-marketing. Cutaneous rashes are the most common manifestations and may be accompanied by systemic symptoms such as fever. In addition, extracutaneous organ involvement, such as drug-induced liver injury (DILI) can also occur, either in combination