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Clin Pharmacol Ther. 2019 Feb;105(2):476-485. doi: 10.1002/cpt.1190. Epub 2018 Sep 30.

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

Author information

1
Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
2
Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan.
3
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
4
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
5
Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
6
Department of Dermatology, Chang Gung Memorial Hospital, Xiamen, China.
7
Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Japan.
8
Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
9
Division of Pharmacogenetics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
10
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
11
Adverse Drug Reaction (ADR) Unit, Pharmacy Department, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
12
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
13
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
14
School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.
15
Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
16
Research Services Center for Health Information, Chang Gung University, Taoyuan, Taiwan.
17
Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan.
18
Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.
19
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taiwan.

Abstract

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.

PMID:
30270535
DOI:
10.1002/cpt.1190

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