HLA-A*2402 May Be Associated With Antiseizure Medication-Induced Severe Mucocutaneous Adverse Events in Korean Population

Dear Editor,Treatment with antiseizure medications (ASMs) is the initial and primary treatment option for patients with epilepsy.Adverse effects are a leading cause of treatment failure during ASM treatment.Not only do they result in early treatment discontinuation in up to 25% of patients, but they also preclude the attainment of fully effective doses and negatively affect patient compliance.Among the adverse effects, idiosyncratic effects cause direct cellular damage by the drug or its metabolites through immune-mediated hypersensitivity reactions, often causing severe cutaneous adverse drug reactions (cADRs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).Many genomic contributors to ASM-induced adverse effects have been suggested, and genes encoding human leukocyte antigen (HLA) molecules are most strongly associated with severe mucocutaneous reactions in patients with epilepsy.1 The first reports demonstrated a strong association between HLA-B*1502 and carbamazepine and other aromatic ASM-induced SJS and TEN in Han Chinese individuals.2 The HLA-A*3101 allele was significantly associated with ASM-induced severe cADRs in the Japanese and European populations.Contrary to the relatively restricted association of HLA-B*1502 with more severe ASM-induced pathologies, HLA-A*3101 has been associated with mild mucocutaneous adverse effects.3 A third HLA allele, HLA-A*2402, has been associated with lamotrigine-induced SJS/TEN and mild maculopapular rash in Han Chinese and mild maculopapular rash in Korean individuals.4,5 Since 2023, we have been conducting a multicenter investigation of the genomic influence of ASM-induced adverse effects in the Korean epilepsy population.Whole-genome sequencing (WGS) was performed using the NovaSeq 6000 platform (Illumina, Inc.).The sequence alignment to hg38 reference sequence and HLA genotyping were performed using nf-core/hlatyping version 24.04.4.5917 (https://nf-co.re/hlatyping/dev/).As of October 2025, among the 171 patients with ASM-induced adverse effects, including cutaneous and non-cutaneous manifestations (e.g., hyponatremia and thrombocytopenia), four were diagnosed with SJS/TEN.The ASMs that caused SJS/TEN were zonisamide in one patient and lamotrigine in three patients.Three patients had the HLA-A*2402 allele and one had the HLA-A*3101 allele.The demographic features and results of the genetic analyses are presented in Table 1.Patient 3 was taking lamotrigine 100 mg twice a day and divalproex sodium 250 mg once a day, and the dosage of the ASMs remained unchanged for 6 months before the onset of SJS.We started zonisamide 50 mg twice a day to control seizures, and SJS occurred after 2 weeks of administration.Consequently, we concluded that zonisamide was the culprit.In a previous study on the HLA association with carbamazepine-induced severe cADRs