HLA Alleles and CYP2C93 as Predictors of Phenytoin Hypersensitivity in East Asians

• Published in: Clinical pharmacology and therapeutics Vol. 105; no. 2; p. 476
• Main Authors: Su, Shih-Chi, Chen, Chun-Bing, Chang, Wan-Chun, Wang, Chuang-Wei, Fan, Wen-Lang, Lu, Lai-Ying, Nakamura, Ryosuke, Saito, Yoshiro, Ueta, Mayumi, Kinoshita, Shigeru, Sukasem, Chonlaphat, Yampayon, Kittika, Kijsanayotin, Pornpimol, Nakkam, Nontaya, Saksit, Niwat, Tassaneeyakul, Wichittra, Aihara, Michiko, Lin, Yu-Jr, Chang, Chee-Jen, Wu, Tony, Hung, Shuen-Iu, Chung, Wen-Hung
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• ISSN: 1532-6535
• DOI: 10.1002/cpt.1190

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 CYP2C9*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 CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.