Oxidative stress and genetic susceptibility to cross-reactive and selective NSAID hypersensitivity

Abstract Aims Nonsteroidal anti inflammatory drugs (NSAIDs) are a leading cause of drug hypersensitivity reactions (HRs), yet genetic determinants of individual susceptibility remain unclear. Growing evidence implicates oxidative stress in these reactions. This study aimed to identify genetic variants in redox and immune related pathways associated with cross reactive NSAID hypersensitivity (CR NSAIDs) and single NSAID induced urticaria/angioedema/anaphylaxis (SNIUAA), and to characterize their functional relevance. Results Genetic association analyses identified significant associations between NSAID HRs and single nucleotide variants (SNVs) in genes involved in redox homeostasis. In CR NSAIDs patients, SNV GSTM5 rs11101989 and GSTZ1 haplotype (rs1046428, rs7975, rs7972) were associated with increased risk of developing HRs, suggesting impaired glutathione dependent detoxification as the underlying factor. Functional analyses demonstrated that carriers of the GSTM5 rs11101989 CC genotype had significantly reduced serum GST activity. In SNIUAA patients, SOD1 variants (rs2070424 and rs2833483) were consistently associated with increased susceptibility and reduced serum superoxide dismutase activity. Additionally, AKR1C3 rs34186955 is also associated with increased susceptibility whereas the variants AKR1C3 rs12529 and IL4R rs1805016 are associated with decreased susceptibility, highlighting the interplay between prostaglandin metabolism, redox regulation, and immune signalling. Innovation Integration of genetic and functional enzymatic validation provides mechanistic evidence that oxidative stress pathways modulate distinct NSAID hypersensitivity phenotypes. Identification of GSTM5 and SOD1 variants with measurable functional impact establishes promising biomarkers to guide personalized risk assessment. Conclusion Genetic variability in oxidative⍰stress and immune regulatory pathways influences susceptibility to cross reactive and selective NSAID hypersensitivity, supporting biomarker based strategies for safer NSAID prescribing.