Abstract | BACKGROUND:
Drug-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. METHODS: 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. RESULTS: CONCLUSIONS: 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.
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Authors | Ana Alfirevic, Faviel Gonzalez-Galarza, Catherine Bell, Klara Martinsson, Vivien Platt, Giovanna Bretland, Jane Evely, Maike Lichtenfels, Karin Cederbrant, Neil French, Dean Naisbitt, B Kevin Park, Andrew R Jones, Munir Pirmohamed |
Journal | Genome medicine
(Genome Med)
Vol. 4
Issue 6
Pg. 51
(Jun 25 2012)
ISSN: 1756-994X [Electronic] England |
PMID | 22732016
(Publication Type: Journal Article)
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