Frontiers in Pharmacology | Genetic Variations in Vitamin D and IgE Receptor Genes Linked to NSAIDs Hypersensitivity Reactions

This study employs targeted exome and 3'UTR analysis to reveal potential associations between single-nucleotide variants in vitamin D pathway genes and high-affinity IgE receptor-related genes with NSAIDs hypersensitivity reactions, providing novel insights into molecular mechanisms and biomarker development for drug hypersensitivity.

 

Literature Overview
This article, "Genetic and serum biomarkers of NSAID hypersensitivity reactions", published in Frontiers in Pharmacology, systematically reviews and summarizes associations between vitamin D-related genes, IgE receptor genes, their genetic variations, and NSAIDs hypersensitivity reactions. The study also measured serum IgE and vitamin D levels to investigate differences across hypersensitivity phenotypes. This research provides potential genetic and immunological foundations for developing improved diagnostic and management strategies.

Background Knowledge
NSAIDs represent a widely used drug class for inflammation and pain relief, but hypersensitivity reactions (HRs) constitute significant clinical challenges, affecting treatment options and increasing healthcare costs. Mechanistically, NSAID HRs are classified into cross-reactive (CR) and selective reaction (SR) types, with SR encompassing IgE-mediated single-drug-induced urticaria/angioedema or anaphylaxis (SNIUAA) and T-cell-mediated reactions. Current understanding of specific immunological mechanisms remains limited, and reliable in vitro diagnostic tools are lacking, making drug challenge tests the gold standard despite inherent risks. Investigating genetic and immunological biomarkers to elucidate mechanisms underlying CR and SR phenotypes holds critical importance for clinical diagnostics and therapeutic approaches.

 

 

Research Methods and Experiments
The study included 1,962 Hispanic individuals: 982 hypersensitivity patients (314 SNIUAA, 668 CR) and 980 tolerant controls (divided into non-atopic and atopic controls). Targeted exome and 3'UTR sequencing analyzed genetic variations across 16 genes related to vitamin D and IgE receptors. Serum IgE and vitamin D levels were measured using standardized immunoassays. A multi-stage analytical approach was implemented, including NGS screening, TaqMan genotyping, and statistical adjustments (Benjamini–Hochberg and Bonferroni corrections) to control for multiple testing errors.

Key Conclusions and Perspectives

• The study identified 216 genetic variants in total, with 186 being novel discoveries. VDR rs78783628, rs739837, rs731236 and CYP24A1 rs2762934 showed significant associations with SNIUAA risk, while FCER1G rs11421 correlated with increased allergic reaction risk in CR-type HR patients.
• After multiple testing adjustments, no significant differences in IgE levels were observed between SNIUAA and CR patients, but RXRB gene haplotypes demonstrated significant associations with elevated IgE levels in both groups.
• Serum vitamin D levels in SNIUAA patients were significantly higher compared to CR patients and non-atopic tolerant individuals, suggesting vitamin D's potential regulatory role across hypersensitivity phenotypes.
• Certain SNVs correlated with specific clinical phenotypes: CYP2R1 rs12794714 and CYP24A1 rs2762934 associated with reduced skin symptom risk, while GC rs139523630 and IL4R rs1801275 linked to increased anaphylaxis risk.
• Although most CR-associated SNVs lost significance after multiple correction, FCER1G rs11421 maintained association with allergic reactions in CR patients, suggesting its role in non-IgE-mediated HRs.

Research Significance and Prospects
This work represents the first systematic analysis of exonic and 3'UTR variations in vitamin D pathway and IgE receptor-related genes in NSAIDs hypersensitivity, identifying potential genetic markers for phenotyping diagnosis and risk stratification. Future research should investigate molecular mechanisms of these variants and validate their prevalence across diverse ethnic populations to advance personalized medicine strategies.

 

 

Conclusion
This study conducted a systematic analysis of genetic associations between vitamin D pathway and IgE receptor genes with NSAIDs hypersensitivity reactions, identifying multiple SNIUAA-associated SNVs including variants in VDR and CYP24A1. RXRB haplotypes showed significant correlations with elevated IgE levels, suggesting regulatory roles in hypersensitivity. While most CR-related variants lost significance after multiple testing corrections, FCER1G rs11421 demonstrated potential influence on allergic reactions in CR patients. Collectively, these findings provide novel genetic biomarker insights and emphasize the importance of immunoregulatory pathways in drug responses, establishing a foundation for future personalized diagnostics and therapeutics.

 

G Amo, J M García-Menaya, M Martí, E García-Martín, and P Ayuso. Genetic and serum biomarkers of NSAID hypersensitivity reactions. Frontiers in Pharmacology.