Nonsteroidal anti-inflammatory drug-induced acute urticaria/angioedema associated with atopy-related genes' genetic variants.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed medicines worldwide and the main drug hypersensitivity triggers. The most common type is bred by pharmacologic cyclooxygenase-1 (COX-1) inhibition, after chemically unrelated NSAID intake, and NSAID-induced acute urticaria/angioedema (NIUA) is the most frequent clinical phenotype, with patients being frequently sensitized (atopic) to Dermatophagoides pteronyssinus (DP). Although NIUA and atopy hold a genetic basis, atopy-related genes have not been previously evaluated in NIUA. In this observational case-control study, we assessed genetic variants in atopy-related genes in NIUA. Tagging single nucleotide polymorphisms in key atopy genes, including cytokines (IL3, IL5, IL9, and the IL4/IL13 region) and receptors (IL4RA and FCER1A), were evaluated in two independent populations of NIUA patients and NSAID-tolerant controls. One thousand two hundred forty individuals were included. Forty-eight tagging single nucleotide polymorphisms were successfully genotyped in the discovery population, with 4 being significantly associated (rs1805010 and rs1801275 in IL4RA, and rs2251746 and rs2494250 in FCER1A). They were further genotyped in the replication population; rs1805010 and rs2494250 remained associated with NIUA. Patients carrying the minor allele of rs1805010 and rs2494250 presented higher total IgE levels than noncarriers (P < .001) and controls (P = .001). NIUA carriers of the rs1805010 minor allele also showed higher levels of DP-specific IgE compared with noncarrier NIUA patients (P = .028) and controls (P < .001). Similar results were found when only atopic NIUA and controls were considered. IL4RA and FCER1A polymorphisms may display a role in NIUA, shedding new light on its relationship with DP sensitization at the molecular level.