D1.371 - Nonsteroidal anti-inflammatory drug-induced acute urticaria/angioedema: antioxidant enzymes activities and associated genetic variants

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed medicines worldwide, and the main drug hypersensitivity reaction triggers. The main NSAID-hypersensitivity type is cross-hypersensitivity (CRH), with patients reacting to at least two chemically unrelated NSAIDs, being NSAID-induced urticaria/angioedema (NIUA) the most common clinical phenotype. These reactions have been associated with alterations in the arachidonic acid pathway due to cyclooxygenase-1 inhibition, which leads to an increase in the synthesis of cysteinyl-leukotrienes by 5-lypoxygenase in susceptible individuals. As both enzymes head oxidative pathways, a potential role for antioxidant enzymes alterations should not be ruled out. In addition, as susceptibility to CRH seems to be under the influence of genetic factors, it is plausible that variants in the main antioxidant defence enzymes could be associated with these reactions. We aimed to evaluate the activity and overall genetic variability in the main enzymes involved in antioxidant defence: superoxide dismutase (SOD)-1, glutathione peroxidase (GPX)-1 and 3, and catalase (CAT).

NIUA patients and controls were recruited in the Allergy Service of the Malaga Regional University Hospital. Enzymatic activities were evaluated by ELISA in cell lysates from NIUA (n=43) and controls (n=18). The genetic variability in CAT, GPX-1 and 3, and SOD-1 was analysed in a Spanish population of NIUA patients (n=247) and controls (n=294) by assessing a set of tagging single nucleotide polymorphisms (tSNPs) using data from Europeans in the 1,000 Genome project.

SOD-1 activity was higher in NIUA patients compared to controls (p=0.038), whereas GPX activity was lower (p=0.036), with no differences for CAT. Twenty-six tSNPs were successfully genotyped in the included population, being 3 significantly associated with NIUA under the additive model: rs3448 in GPX-1 (OR=0.61, IC=0.45-0.83, p=0.037), rs3792798 (OR=0.47, IC=0.29-0.75, p=0.024) in GPX-3, and rs10432782 in SOD-1 (OR=1.6, IC=1.21-2.13, p=0.022). No changes in activities were found regarding the specific genotypes.

Although preliminary, our results provide new insights into the underlying mechanisms in NSAID-CRH, suggesting a role for antioxidant enzymes in NIUA. Nevertheless, more studies are needed to validate these results in other populations, as well as to establish their relevance at the molecular level.