123: Pharmacogenomics of β-lactam Antibiotic-induced Severe Cutaneous Adverse Reactions

Statement of Purpose: β-lactam antibiotics are widely prescribed and are one of the most common drug classes to induce unexpected serious adverse reactions, particularly severe cutaneous adverse reactions (SCARs). SCARs, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are life-threatening events with mortality rates up to 70%. Even if patients survive, they frequently suffer from both physical and psychological long-term sequelae. There are known genetic predispositions to SCAR from several drugs, but it is unclear whether this exists in β-lactam antibiotics.

Description of Methods & Materials: 196 β-lactam exposed patients, including 30 SCAR cases and 166 tolerant controls, were recruited across nine Canadian Academic Health Centres between 2005 and 2022. The phenotypes of SCARs were classified according to the consensus definitions of the RegiSCAR study criteria. Relevant demographic characteristics, including age, sex, and antibiotic regimens, were identified. All patients were genotyped using a custom Illumina Global Screening Array plus Multi-Disease add-on content. Genome-wide analysis was then performed using allelic association tests.

Data & Results: Genome-wide analysis demonstrated two genetic variants that were significantly associated with β-lactam antibiotics-induced SCARs. One variant near the WDR11 gene was found in 20% of cases (n=6) compared with only one out of 166 controls (0.6%) with an odds ratio (OR) of 43.7 (95%CI: 5.3-362.5; p value: 1.0x10-8). Another variant near the CDIN1 gene was present in 12 out of 30 cases (40%) compared to 9 out of 166 controls (5.4%) (OR (95% CI): 8.97 (3.6-22.4); p value: 4.1x10-8).

Interpretation, Conclusion or Significance: The WDR11 gene is involved in the Hedgehog signaling pathway and contributes to epidermal development and repair. The CDIN1 gene is part of keratinocyte expression clusters with a role in epithelial cell function. These findings suggest a role of these genes in the biology underlying β-lactam antibiotics-induced severe skin adverse reactions.

Disclosures: None