Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

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 basi...

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Published in:JAMA : the journal of the American Medical Association Vol. 312; no. 5; p. 525
Main Authors: Chung, Wen-Hung, Chang, Wan-Chun, Lee, Yun-Shien, Wu, Ying-Ying, Yang, Chih-Hsun, Ho, Hsin-Chun, Chen, Ming-Jing, Lin, Jing-Yi, Hui, Rosaline Chung-Yee, Ho, Ji-Chen, Wu, Wei-Ming, Chen, Ting-Jui, Wu, Tony, Wu, Yih-Ru, Hsih, Mo-Song, Tu, Po-Hsun, Chang, Chen-Nen, Hsu, Chien-Ning, Wu, Tsu-Lan, Choon, Siew-Eng, Hsu, Chao-Kai, Chen, Der-Yuan, Liu, Chin-San, Lin, Ching-Yuang, Kaniwa, Nahoko, Saito, Yoshiro, Takahashi, Yukitoshi, Nakamura, Ryosuke, Azukizawa, Hiroaki, Shi, Yongyong, Wang, Tzu-Hao, Chuang, Shiow-Shuh, Tsai, Shih-Feng, Chang, Chee-Jen, Chang, Yu-Sun, Hung, Shuen-Iu
Format: Journal Article
Language:English
Published: United States 06.08.2014
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Anticonvulsants - adverse effects
Anticonvulsants - pharmacokinetics
Aryl Hydrocarbon Hydroxylases - genetics
Case-Control Studies
Cytochrome P-450 CYP2C9
Eosinophilia - chemically induced
Eosinophilia - genetics
Female
Genome-Wide Association Study
Humans
Japan
Malaysia
Male
Middle Aged
Pharmacogenetics
Phenytoin - adverse effects
Phenytoin - pharmacokinetics
Polymorphism, Single Nucleotide
Stevens-Johnson Syndrome - genetics
Taiwan
Young Adult
Japan
Malaysia
Taiwan
ISSN:1538-3598, 1538-3598
Online Access:Get more information
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Summary: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. To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. 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. Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. 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. 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.
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ISSN:1538-3598
1538-3598
DOI:10.1001/jama.2014.7859