| Summary: | Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen <i>(HLA)-B*15:02</i> is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and <i>CYP2C9*3</i> with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (<i>CYP2C9*3</i>) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the <i>HLA B*51:01</i> and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that <i>CYP2C9*3</i> was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, <i>p</i> = 003). In subgroup analysis, <i>CYP2C9*3</i> and <i>HLA B*55:01</i> were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, <i>p</i> = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, <i>p</i> = 0.035), respectively. Pooled data analysis has confirmed the association between <i>HLA B*51:01</i>/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, <i>p</i> = <0.001) and <i>HLA B*51:01/</i>PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, <i>p</i> = 0.037). In this study, neither the case nor the control groups had any patients with <i>HLA B*15:02</i>. The risk variables for PHT-SCAR<i>s,</i> PHT-overall CADRs, and PHT-MPE were found to be <i>HLA B*51:01, CYP2C9*3,</i> and <i>HLA B*55:01</i>, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size.
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