Pharmacogenetic Determinants of Immediate and Delayed Reactions of Drug Hypersensitivity

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 beta-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 FcepsilonRIbeta 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 FcepsilonRIalpha 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.

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

“…The several studies reported in Europe, China, and US converged in showing that AR to BLs are influenced by genes that are involved in IgE production, including those of the IL13 and IL4 pathways (14,16,18,20,60). The association between immediate allergic reactions to BLs and polymorphisms of IL13 (R130Q and À1055C>T variants), IL4R (I50V, S478P, and Q551R variants) has been evaluated in patients and their matched control subjects from central Italy and the south of Spain (16).…”

The Genetics of Drug Hypersensitivity Reactions

“…However, many studies have included limited numbers of individuals, often without replication, and largely in populations of Asian descent [85][86][87].…”

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs

“…However, many studies [19][20][21] have included limited numbers of individuals, often without replication, largely in Asian populations. Overall, there is a lack of consistent genetic markers for HDRs to NSAIDs.…”