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HLA and the Pharmacogenomics of Drug Hypersensitivity

White, K.D., Gaudieri, S. and Phillips, E.J. (2014) HLA and the Pharmacogenomics of Drug Hypersensitivity. In: Padmanabhan, S., (ed.) Handbook of Pharmacogenomics and Stratified Medicine. Elsevier, pp. 437-465.

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Adverse drug reactions (ADRs) represent a tremendous source of morbidity, mortality and cost in modern medicine. The human leukocyte antigen (HLA) genes are highly polymorphic and encode proteins that are integral to T-cell-mediated immunity to infectious pathogens. A growing body of data demonstrates that T-cell immune responses are also etiologic for many ADRs and that certain HLA genotypes predispose to the development of drug hypersensitivity. Well-characterized examples of HLA-associated drug hypersensitivity reactions include those involving abacavir, carbamazepine, allopurinol, nevirapine, flucloxacillin, and amoxicillin-clavulanate. The mechanisms underlying HLA-associated ADRs are the subject of exciting research and recent findings have identified key interactions between small molecule pharmaceuticals and HLA proteins thereby elucidating the immunopathogenesis of certain ADRs. Drug hypersensitivity preventive strategies developed as part of this work, such as stratified approaches to avoid abacavir in all those carrying HLA-B*57:01, have been translated from discovery into routine clinical use. In the future it is predicted that our enhanced understanding of HLA-drug interactions will lead to the successful implementation of high-throughput preclinical and early premarketing drug toxicity screening approaches that will lead to safer and more effective drug design and development.

Item Type: Book Chapter
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Elsevier
Copyright: © 2014 Elsevier Inc.
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