RT Journal Article
T1 Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema
A1 Jurado-Escobar, Raquel
A1 Doña, Inmaculada
A1 Triano-Cornejo, José
A1 Perkins, James R.
A1 Pérez-Sánchez, Natalia
A1 Testera-Montes, Almudena
A1 Labella, Marina
A1 Bartra, Joan
A1 Laguna, José J.
A1 Estravís, Miguel
A1 Agúndez, José A.G.
A1 Torres, María J.
A1 Cornejo-García, José A.
K1 NSAID cross-hypersensitivity
K1 Urticaria/angioedema
K1 Cytosolic phospholipase A2
K1 Polymorphisms
K1 Arachidomic acid
AB 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.
PB Frontiers
YR 2021
FD 2021-04-30
LK http://hdl.handle.net/10668/3525
UL http://hdl.handle.net/10668/3525
LA en
NO Jurado-Escobar R, Doña I, Triano-Cornejo J, Perkins JR, Pérez-Sánchez N, Testera Montes A, et al. Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug–Induced Acute Urticaria/Angioedema. Frontiers in Pharmacology. 2021, Vol 12, January.
DS RISalud
RD Apr 10, 2025