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


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.
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, The Waterhouse Building, Brownlow Street 1-5, Liverpool, L69 3GL, UK. Ana.Alfirevic@liv.ac.uk.
Ana
A
Alfirevic
Faviel
F
Gonzalez-Galarza
Catherine
C
Bell
Klara
K
Martinsson
Vivien
V
Platt
Giovanna
G
Bretland
Jane
J
Evely
Maike
M
Lichtenfels
Karin
K
Cederbrant
Neil
N
French
Dean
D
Naisbitt
B Kevin
BK
Park
Andrew R
AR
Jones
Munir
M
Pirmohamed