Genetic Variants Associated with Non-Steroidal Anti-Inflammatory Drug-Induced Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

<b>Background/Objectives</b>: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to help alleviate pain and treat inflammation, but they are also recognized as common causes of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite their clinical importance, pharmacogenetic markers to predict individual susceptibility to NSAID-induced SJS/TEN remain insufficiently defined. This study investigated associations between <i>HLA</i> class I and II alleles, <i>CYP2C9</i> polymorphisms, and NSAID-induced SJS/TEN in a Thai population. <b>Methods</b>: A total of 18 patients with NSAID-induced SJS/TEN and 54 NSAID-tolerant controls were enrolled. Genotype data from 183 unrelated Thai individuals without a history of drug allergy were included as a general population control group. Genotyping was performed for <i>HLA</i> class I and II alleles and the <i>CYP2C9*3</i> variant. <b>Results</b>: <i>HLA-DQB1*03:02</i> was significantly associated with NSAID-induced SJS/TEN (OR = 9.23, 95% CI = 2.19-38.83, <i>p</i> = 0.0024, Pc = 0.0312), particularly those triggered by piroxicam (OR = 13.71, 95% CI = 2.81-66.86, <i>p</i> = 0.0012, Pc = 0.0156). Additional associations were identified for <i>HLA-B*56:01</i> and <i>HLA-A*68:01</i> in the overall NSAID-induced SJS/TEN group. The subgroup analysis suggested that these alleles, along with <i>HLA-DRB1*04:03</i>, were associated with an increased risk of piroxicam-induced SJS/TEN. However, these associations did not remain statistically significant after Bonferroni's correction. No significant association was identified for <i>CYP2C9*3</i>. <b>Conclusions</b>: This study identified specific <i>HLA</i> alleles, particularly <i>HLA-DQB1*03:02</i>, as candidate pharmacogenetic risk factors for NSAID-induced SJS/TEN in a Thai population, especially in piroxicam-associated cases. However, these associations should be considered exploratory. Larger, multicenter, multi-ethnic studies are required to validate these findings and clarify their potential clinical utility.