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

Abstract

Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membranespanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure.Allergy 71 (2016) 443-462

Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross‐Reactive Nonsteroidal Anti‐inflammatory Drug Hypersensitivity

“…In the last decade the most frequent studies related to genetic factors affecting hypersensitivity to NSAIDs have included leukotriene synthesis and drug metabolism enzymes such as cytochrome P450 isoenzymes, diamino oxidase, and HLA genes. 16 Although it is thought that leukotriene overproduction is the main nonallergic mechanism found in hypersensitivity to NSAIDs, there are some events that occur in nonallergic hypersensitivity to NSAIDs cases that are not explained by this type of mechanism. For instance, antihistamine administration is necessary for therapeutic management, although the mechanism of histamine secretion is unknown.…”

Progress in understanding hypersensitivity reactions to nonsteroidal anti‐inflammatory drugs

“…In addition to the potential biomarkers described, here we highlight the potential utility of transcriptomics and metabolomics to disentangle NSAIDs hypersensitivity underlying mechanisms. Although providing extensive data on the genetics of NSAIDs hypersensitivity is out of our scope as a recent PRISMA‐compliant systematic review is available, some information is included. Unfortunately, data from transcriptomics and metabolomics in NSAIDs hypersensitivity are limited (Table ).…”

Update on the Genetic Basis of Drug Hypersensitivity Reactions

“…They have mainly been performed in populations with Asian ancestry and include a limited number of patients, generally without a second population for replication [11,75,76].…”

“…Consequently, we are far from identifying clinically proven genetic biomarkers. Additional associated difficulties in the study of these reactions include ethnic variation, differences in the definition of clinical phenotypes between different groups, and noninclusion of additional populations for replication purposes in most studies [10,11].…”