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

Abstract

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 1Á7 for rs10306194 [95% confidence interval (CI) 1Á34-2Á14; P corrected = 2Á83 9 10 -4 ) and 2Á19 for rs28395868 (95% CI 1Á43-3Á36; P corrected = 0Á002). 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.

Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients

“…The analysis of associations with atherosclerosis measurements revealed that PTGS1 rs10306194, tagging the distal region of the gene coding for COX1, was the most relevant SNP, as the variant genotypes were linked to increased presence of plaque in the carotid, higher atherosclerosis severity score and accelerated ccIMT progression. This tag-SNP has not been widely studied, but one report has regarded it as clinically relevant, after being solidly associated with acute urticaria/angioedema 19 . This polymorphism produces an A-to-T change in the 3′-untranslated (UTR) region of PTGS1 whose functional relevance, however, is yet to be elucidated.…”

Biomarkers of immediate drug hypersensitivity

“…115 Available data show that NECD and NIUA share similar genetic backgrounds; nevertheless, different gene polymorphisms have been reported. 117,118…”

“…In NERD, variants in genes associated with LT production (5‐Lipoxygenase, 5‐LOX) and LTC4 synthase and PGs production (COX) pathways were reported 115 . Available data show that NECD and NIUA share similar genetic backgrounds; nevertheless, different gene polymorphisms have been reported 117,118 …”

Levels of serum inflammatory cytokines and their correlations with disease severity in patients with chronic spontaneous urticaria

“…In addition, CSU patients’ serum can also detect some autoantibodies, such as anti-thyroid peroxidase antibody and anti-cell membrane antibody, and the production of these autoantibodies is also closely related to the inflammatory response [ 9 , 10 ]. For CSU, antihistamines are currently the main treatment method [ 11 ]. However, for some patients, antihistamines may not alleviate their symptoms very well.…”