Pharmacogenetic determinants of immediate and delayed reactions of Drug hypersensitivity

Jean Louis Guéant, R. M. Guéant-Rodriguez, I. Aimore Gastin, J. A. Cornejo-García, M. Viola, A. Barbaud, P. M. Mertes, M. Blanca, Antonio Romano

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Abstract

Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in β-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcεRIβ gene). Delayed T-cell- mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcεRIα gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.

Original languageEnglish
Pages (from-to)2770-2777
Number of pages8
JournalCurrent Pharmaceutical Design
Volume14
Issue number27
DOIs
Publication statusPublished - 2008

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Keywords

  • β-Lactams
  • Abacavir
  • Aspirin
  • Drug allergy
  • Drug hypersensitivity
  • Gene polymorphism
  • Pharmacogenetics
  • Sulfamethoxazole

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Guéant, J. L., Guéant-Rodriguez, R. M., Gastin, I. A., Cornejo-García, J. A., Viola, M., Barbaud, A., Mertes, P. M., Blanca, M., & Romano, A. (2008). Pharmacogenetic determinants of immediate and delayed reactions of Drug hypersensitivity. Current Pharmaceutical Design, 14(27), 2770-2777. https://doi.org/10.2174/138161208786369795