Polymorphisms in eicosanoid‐related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti‐inflammatory drug hypersensitivity. (5th July 2021)

• Record Type: Journal Article
• Authors: Jurado‐Escobar, R.; Doña, I.; Perkins, J.R.; Laguna, J.J.; Muñoz‐Cano, R.; García‐Sánchez, A.; Ayuso, P.; Torres, M.J.; Mayorga, C.; Cornejo‐García, J.A.
• Is Part Of: British journal of dermatology. Volume 185:Number 4(2021)
• Page Start: 815
• Page End: 824
• Publication Date: 2021-07-05
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.20440
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID‐induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 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 be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. Objectives: To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. Methods: Two independent cohorts of patients were recruited in Spain, alongside NSAID‐tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID‐exacerbated respiratory disease (NERD). A set of tagging single‐nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. Results: The study included 1272 individuals. Thirty‐five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1 ; rs28395868 in ALOX5 ). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34–2·14; P corrected = 2·83 × 10 –4 ) and 2·19 for rs28395868 (95% CI 1·43–3·36; P corrected = 0·002). Conclusions: Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID‐hypersensitivity and shedding light on their genetic basis. Abstract : What is already known about this topic? Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions, with skin the most frequently affected organ. The underlying mechanism is linked to cyclooxygenase (COX)‐1 inhibition and to imbalance in eicosanoid metabolism (mainly prostaglandins and cysteinyl leukotriene). The idiosyncratic nature of NSAID hypersensitivity supports the involvement of genetic factors. No study has simultaneously evaluated the potential role of genetic variants in the main eicosanoid synthesis enzymes in these reactions. What does this study add? rs10306194 ( PTGS1 ) and rs28395868 ( ALOX5 ) were associated with the risk of NSAID‐induced acute urticaria/angioedema in two independent populations, with the latter also being associated with NSAID‐exacerbated respiratory disease. rs10306194 could help to discriminate those with NIUA from those whose respiratory symptoms are exacerbated after NSAID intake. Our results add credence to the COX‐1 inhibition hypothesis in NSAID hypersensitivity and could help to differentiate its clinical phenotypes. What is the translational message? Diagnosis of NSAID hypersensitivity is a daily challenge in clinical settings as there is a lack of in vivo and in vitro tests, and drug provocation is not a risk‐free procedure. Genetic research can provide substantial information not only to understand fully the underlying mechanism, but also to identify potential biomarkers for diagnosis and to develop targeted precision therapies. Linked Comment: C. Flores. Br J Dermatol 2021; 185 :697–698 .