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

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• 作者：Ana Alfirevic (1)
  Faviel Gonzalez-Galarza (2)
  Catherine Bell (3)
  Klara Martinsson (3) (4)
  Vivien Platt (1) (3)
  Giovanna Bretland (1)
  Jane Evely (1)
  Maike Lichtenfels (1)
  Karin Cederbrant (4)
  Neil French (3)
  Dean Naisbitt (3)
  B Kevin Park (1) (3)
  Andrew R Jones (2)
  Munir Pirmohamed (1)
  
• 刊名：Genome Medicine
• 出版年：2012
• 出版时间：June 2012
• 年：2012
• 卷：4
• 期：6
• 全文大小：
• 作者单位：Ana Alfirevic (1)
  Faviel Gonzalez-Galarza (2)
  Catherine Bell (3)
  Klara Martinsson (3) (4)
  Vivien Platt (1) (3)
  Giovanna Bretland (1)
  Jane Evely (1)
  Maike Lichtenfels (1)
  Karin Cederbrant (4)
  Neil French (3)
  Dean Naisbitt (3)
  B Kevin Park (1) (3)
  Andrew R Jones (2)
  Munir Pirmohamed (1)
  
  1. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, The Waterhouse Building, Brownlow Street 1-5, Liverpool, L69 3GL, UK
  2. Department of Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7ZB, UK
  3. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, The Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK
  4. Safety Assessment, AstraZeneca, Gartuna, S?dert?lje, Sweden
  
• ISSN：1756-994X

文摘

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.