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

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.

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…6,[25][26][27][28] In contrast, flucloxacillin does not alter peptide binding to HLA-B*57:01, 28 which supports our hypothesis that functional flucloxacillin antigens derive from naturally processed drug-protein conjugates. Flucloxacillin-responsive CD8þ clones from patients with liver injury and HLA-B*57:01-positive volunteers were not stimulated with abacavir.…”

Origin of Ancient Canary Islanders Guanches: presence of Atlantic/Iberian HLA and Y chromosome genes and Ancient Iberian language

“…(Imanishi et al, 1991c), Wales (Darke et al, 1998) and Northwest England (Alfirevic et al, 2012). Then, Tenerife Island population may seem to be related to both Mediterranean and Atlantic populations.…”

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…To explore possible haplotype associations, we have recently used an in silico approach to analyze data stored in our database and in public repositories. We found that (1) different HLA alleles associated with druginduced liver injury are in strong linkage disequilibrium in populations of Caucasian and non-Caucasian ancestry, and (2) HLA risk alleles associated with unrelated drugs, such as flucloxacillin, ximelagatran, lapatinib, and antituberculosis drugs, reside on two main haplotypes (Alfirevic et al, 2012). Investigations are now clearly needed with lymphocytes from HLAtyped patients to investigate the immune mechanism (s) in different forms of HLA class II-associated IDRs.…”