The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions

The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions Genetic polymorphism in the genes encoding the human leukocyte antigen (HLA) molecules enables presentation of a wide range peptide ligands thus maximising immune surveillance of pathogens. A consequence of the diversification of the HLA Ag-binding pocket is the enhanced opportunity for off-target binding of small drugs by HLA molecules, with subsequent immune reactivity. These potential off-target interactions are ‘set up’ to generate T cell-mediated adverse drug reactions even though the precise mechanisms of most HLA-drug interactions are still poorly understood. The association between abacavir hypersensitivity syndrome and HLA-B*57:01 is one exception that has been resolved at a molecular and mechanistic level. Here, we explore the road to understanding the interaction between abacavir and the HLA-B*57:01 molecule and review the current state of understanding of interactions between other drugs and HLA molecules implicated in adverse drug reactions, which appear to involve multiple mechanisms. The continued expansion of the pharmacopoeia generates an imperative to understand these interactions at the molecular level in order to prevent the continued burden on individuals and the health care system. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Immunogenetics Springer Journals

The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions

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Publisher
Springer Berlin Heidelberg
Copyright
Copyright © 2017 by Springer-Verlag Berlin Heidelberg
Subject
Biomedicine; Immunology; Human Genetics; Gene Function; Cell Biology; Allergology
ISSN
0093-7711
eISSN
1432-1211
D.O.I.
10.1007/s00251-017-1007-5
Publisher site
See Article on Publisher Site

Abstract

Genetic polymorphism in the genes encoding the human leukocyte antigen (HLA) molecules enables presentation of a wide range peptide ligands thus maximising immune surveillance of pathogens. A consequence of the diversification of the HLA Ag-binding pocket is the enhanced opportunity for off-target binding of small drugs by HLA molecules, with subsequent immune reactivity. These potential off-target interactions are ‘set up’ to generate T cell-mediated adverse drug reactions even though the precise mechanisms of most HLA-drug interactions are still poorly understood. The association between abacavir hypersensitivity syndrome and HLA-B*57:01 is one exception that has been resolved at a molecular and mechanistic level. Here, we explore the road to understanding the interaction between abacavir and the HLA-B*57:01 molecule and review the current state of understanding of interactions between other drugs and HLA molecules implicated in adverse drug reactions, which appear to involve multiple mechanisms. The continued expansion of the pharmacopoeia generates an imperative to understand these interactions at the molecular level in order to prevent the continued burden on individuals and the health care system.

Journal

ImmunogeneticsSpringer Journals

Published: Jul 10, 2017

References

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