PMID- 22732016
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121129
LR  - 20220129
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 4
IP  - 6
DP  - 2012 Jun 25
TI  - In silico analysis of HLA associations with drug-induced liver injury: use of a 
      HLA-genotyped DNA archive from healthy volunteers.
PG  - 51
LID - 10.1186/gm350 [doi]
AB  - 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.
FAU - Alfirevic, Ana
AU  - Alfirevic A
AD  - 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.
FAU - Gonzalez-Galarza, Faviel
AU  - Gonzalez-Galarza F
FAU - Bell, Catherine
AU  - Bell C
FAU - Martinsson, Klara
AU  - Martinsson K
FAU - Platt, Vivien
AU  - Platt V
FAU - Bretland, Giovanna
AU  - Bretland G
FAU - Evely, Jane
AU  - Evely J
FAU - Lichtenfels, Maike
AU  - Lichtenfels M
FAU - Cederbrant, Karin
AU  - Cederbrant K
FAU - French, Neil
AU  - French N
FAU - Naisbitt, Dean
AU  - Naisbitt D
FAU - Park, B Kevin
AU  - Park BK
FAU - Jones, Andrew R
AU  - Jones AR
FAU - Pirmohamed, Munir
AU  - Pirmohamed M
LA  - eng
GR  - G0700654/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20120625
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
PMC - PMC3698530
EDAT- 2012/06/27 06:00
MHDA- 2012/06/27 06:01
PMCR- 2012/06/25
CRDT- 2012/06/27 06:00
PHST- 2011/10/31 00:00 [received]
PHST- 2012/04/20 00:00 [revised]
PHST- 2012/06/25 00:00 [accepted]
PHST- 2012/06/27 06:00 [entrez]
PHST- 2012/06/27 06:00 [pubmed]
PHST- 2012/06/27 06:01 [medline]
PHST- 2012/06/25 00:00 [pmc-release]
AID - gm350 [pii]
AID - 10.1186/gm350 [doi]
PST - epublish
SO  - Genome Med. 2012 Jun 25;4(6):51. doi: 10.1186/gm350.