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JAMA. 2014 Aug 6;312(5):525-34. doi: 10.1001/jama.2014.7859.

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

Author information

1
Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwa.
2
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
3
Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan.
4
Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
5
Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
6
College of Medicine, Chang Gung University, Taoyuan, Taiwan6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
7
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan7Department of Dermatology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
8
College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.
9
College of Medicine, Chang Gung University, Taoyuan, Taiwan9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
10
College of Medicine, Chang Gung University, Taoyuan, Taiwan10Department of Pharmacy, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
11
College of Medicine, Chang Gung University, Taoyuan, Taiwan11Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.
12
Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Johor, Malaysia.
13
Department of Dermatology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
14
Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
15
Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.
16
Department of Pediatrics, China Medicine University, Taichung, Taiwan.
17
Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
18
Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
19
Department of Dermatology, Course of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
20
Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China.
21
College of Medicine, Chang Gung University, Taoyuan, Taiwan21Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou, Taiwan22Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.
22
College of Medicine, Chang Gung University, Taoyuan, Taiwan23Department of Plastic Surgery and Burn Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
23
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
24
College of Medicine, Chang Gung University, Taoyuan, Taiwan25Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
25
Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.

Abstract

IMPORTANCE:

The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown.

OBJECTIVE:

To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

DESIGN, SETTING, AND PARTICIPANTS:

Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia.

MAIN OUTCOMES AND MEASURES:

Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

RESULTS:

The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease.

CONCLUSIONS AND RELEVANCE:

This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

PMID:
25096692
DOI:
10.1001/jama.2014.7859
[Indexed for MEDLINE]

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