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 ) 2C9*3 , we found that HLA ‐B*13:01 , HLA ‐B*15:02 , and HLA ‐B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP 2C9*3 / HLA ‐B*13:01 / HLA ‐B*15:02 / HLA ‐B*51:01 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 CYP 2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.