Epilepsy ranks as the second most common neurological disorder worldwide, manifesting through recurrent, unprovoked, and self-limiting seizures that may have genetic, acquired, or unknown causes. This review focused on identifying pharmacogenomic markers linked to hypersensitivity reactions triggered by aromatic antiseizure medications. It addressed the pharmacokinetics and pharmacogenomics of CYP2C9 and HLA genes, explored immunopathogenic mechanisms, and discussed the clinical significance of these associations. Studies included in this review reported results using odds ratios (OR), 95% confidence intervals (95% CI), and p-values to assess links with severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Notably, CYP2C192 was associated with SCARs induced by carbamazepine, phenytoin, and phenobarbital. Five studies linked CYP2C93 to phenytoin-related SCARs, while several studies further implicated CYP2C93 and HLA alleles (HLA-B13:01, HLA-B15:02, HLA-B51:01, HLA-B55:01, HLA-B46:01, HLA-B56:02/04) in phenytoin-induced hypersensitivity. HLA-B15:02 was reported in six studies as a key risk factor for carbamazepine-induced SJS/TEN, whereas lamotrigine-induced SCARs were associated in four studies with HLA-A02:07, HLA-A24:02, HLA-A33:03, HLA-B15:02, and HLA-B44:03. Additionally, one study linked HLA-A02:01, HLA-B35:01, HLA-C04:01, and HLA-C08:01 to SCARs from lamotrigine and phenytoin, and three studies identified HLA-A02:01, HLA-A11:01, HLA-A24:02, HLA-B15:02, HLA-B38:01, HLA-B40:02, and HLA-DRB103:01 in SCARs induced by carbamazepine, lamotrigine, and phenytoin. Collectively, evidence highlights CYP2C9*3 and multiple HLA alleles as significant predictors of severe cutaneous reactions such as TEN and SJS, suggesting these variants could serve as actionable genetic biomarkers to prevent serious adverse effects from carbamazepine, phenytoin, phenobarbital, and lamotrigine, especially in Asian populations.
