HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians.

To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C93, we found that HLA-B13:01, HLA-B15:02, and HLA-B51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C93/HLA-B13:01/HLA-B15:02/HLA-B51:01 from 30.5-71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.