Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

Nonsteroidal anti-inflammatory drugs (NSAIDs), probably the most consumed medicines, are the main triggers of drug hypersensitivity, being NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID-hypersensitivity is bred by cyclooxygenase (COX)-1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl-leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID-hypersensitivity, genetic factors are believed to participate; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID-hypersensitivity.We aimed to simultaneously evaluate genetic variants in main genes involved in PG and CysLT biosynthesis in NIUA.Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort only included NIUA patients; the replication one also included NSAID-exacerbated respiratory disease (NERD) patients. A set of tagging single nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX-5 and LTC4S was genotyped using mass spectrometry coupled with end point PCR.The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, being three significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1, and rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 marginally with NERD. Effect sizes in the combined analysis (discovery and replication NIUA populations) were: rs10306194 (OR=1.7, 95%CI=1.34-2.14; corrected p-value=2.44E-5) and rs28395868 (OR=2.19, 95%CI=1.43-3.36, corrected p-value=2.17E-4).PTGS1 and ALOX5 gene variants may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light into their genetic basis.

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Authors: R Jurado-Escobar, I Doña, J R Perkins, J J Laguna, R Muñoz-Cano, A García-Sánchez, P Ayuso, M J Torres, C Mayorga, J A Cornejo-García