Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most highly consumed medicines worldwide because of their efficiency in the treatment of pain and different inflammatory conditions (Fosbøl et al, 2008; Conaghan, 2012; Duong et al, 2014)
Mean age for NSAID-induced acute urticaria/angioedema (NIUA) subjects was 41 ± 15 years and 42.6 ± 13.6 years for controls from the discovery population (p 0.191), whereas in the replication population, mean age for NIUA was 41.7 ± 15 years and 42.7 ± 11.6 years for controls (p 0.033). According to their clinical history, more than 80% of NIUA patients had suffered at least three reactions of crosshypersensitivity to NSAIDs; final diagnosis was established in all patients on the basis of a positive a positive salicylic acid (ASA)-DPT, as described (Doña et al, 2018)
Through the pharmacological inhibition of the COX-1 enzyme, PG production is blocked, and the arachidonic acid (AA) metabolic pathway is shunted toward the biosynthesis of CysLTs
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most highly consumed medicines worldwide because of their efficiency in the treatment of pain and different inflammatory conditions (Fosbøl et al, 2008; Conaghan, 2012; Duong et al, 2014). NSAIDs trigger the 21–25% of all adverse drug reactions, which includes hypersensitivity to drugs (Kowalski et al, 2011). NSAID-induced acute urticaria/angioedema (NIUA), a phenotype characterized by wheals and/or angioedema development in patients without chronic spontaneous urticaria (CSU), is the most frequent clinical entity (Dona et al, 2012; Kowalski et al, 2013; Dona et al, 2014; Doña et al, 2020). NSAID cross-hypersensitivity reactions are not mediated by an immunological mechanism but associated with the pharmacological inhibition of cyclooxygenase-1 (COX-1) and increased of cysteinyl-leukotriene (CysLT) levels. COX-1 inhibition blocks PG synthesis, leading to an increased transformation of arachidonic acid (AA) into LTA4, which is metabolized to LTC4 and LTE4 (Doña et al, 2020). COX-1 inhibition by NSAIDs shunts the AA pathway from PG toward CysLT synthesis, eliciting a reaction in susceptible individuals (Doña et al, 2020)
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