HLA-A*32:01 and Lamotrigine-Induced Drug Reaction With Eosinophilia and Systemic Symptoms

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, potentially fatal hypersensitivity syndrome with 3% to 10% mortality, and lamotrigine, a first-line treatment for bipolar and seizure disorders, is among the top 5 causative agents of DRESS in the United States and globally. Commercial panels test HLA-B*15:02 and HLA-A*31:01 for risk of carbamazepine-associated severe cutaneous adverse reactions; however, these are not validated for lamotrigine-induced DRESS, and current reports from these commercial assays could therefore provide false reassurance. No HLA associations with lamotrigine-induced DRESS have been established in US populations. Objective: To identify HLA genetic variants associated with lamotrigine-induced DRESS in a US population. Design, Setting, and Participants: This matched case-control study was conducted at 2 US academic medical centers (Vanderbilt University Medical Center and Mass General Brigham). Patients with lamotrigine-induced DRESS confirmed by Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria (score ≥4) were prospectively enrolled between April 2016 and June 2025. Lamotrigine-tolerant controls were matched 10:1 from the Vanderbilt BioVU biobank on sex, self-reported race, and age. HLA typing included class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1) loci for case (high-resolution typing) and control (imputed from genotyping array data) participants. Main Outcomes and Measures: HLA class I and II alleles and haplotypes were tested using logistic regression with Bonferroni correction for their association with lamotrigine-induced DRESS. Results: This study included 29 patients with lamotrigine-induced DRESS (case participants; median [IQR] age, 33 [24-56] years; 25 female [86.2%]; 2 Asian [6.9%], 2 Black [6.9%], 23 White [79.3%], and 2 unknown race [6.9%]) and 290 matched control participants. HLA-A*32:01 was associated with lamotrigine-induced DRESS (41.4% [12 case participants] vs 4.1% [12 control participants]; odds ratio [OR], 16.4; 95% CI, 6.4-42.5; Bonferroni-corrected P < .001). No other alleles or class II loci showed significant associations after correction. The A*32:01 ~ B*44:02 haplotype was enriched (OR, 18.4; 95% CI, 4.6-83.8; Bonferroni-corrected P = .001) in lamotrigine-induced DRESS. Conclusions and Relevance: In this case-control study, HLA-A*32:01 was associated with lamotrigine-induced DRESS in a US population. Given that HLA-A*32:01 is not included in existing commercial pharmacogenomic panels, adding this marker could improve preprescription DRESS risk identification for lamotrigine.