Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

Wen Hung Chung; Wan Chun Chang; Yun Shien Lee; Ying Ying Wu; Chih Hsun Yang; Hsin Chun Ho; Ming Jing Chen; Jing Yi Lin; Rosaline Chung Yee Hui; Ji Chen Ho; Wei Ming Wu; Ting Jui Chen; Tony Wu; Yih Ru Wu; Mo Song Hsih; Po Hsun Tu; Chen Nen Chang; Chien Ning Hsu; Tsu Lan Wu; Siew Eng Choon; Chao Kai Hsu; Der Yuan Chen; Chin San Liu; Ching Yuang Lin; Nahoko Kaniwa; Yoshiro Saito; Yukitoshi Takahashi; Ryosuke Nakamura; Hiroaki Azukizawa; Yongyong Shi; Tzu Hao Wang; Shiow Shuh Chuang; Shih Feng Tsai; Chee Jen Chang; Yu Sun Chang; Shuen Iu Hung

doi:10.1001/jama.2014.7859

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

Wen Hung Chung
, Wan Chun Chang
, Yun Shien Lee
, Ying Ying Wu
, Chih Hsun Yang
, Hsin Chun Ho
, Ming Jing Chen
, Jing Yi Lin
, Rosaline Chung Yee Hui
, Ji Chen Ho
, Wei Ming Wu
, Ting Jui Chen
, Tony Wu
, Yih Ru Wu
, Mo Song Hsih
, Po Hsun Tu
, Chen Nen Chang
, Chien Ning Hsu
, Tsu Lan Wu
, Siew Eng Choon

Chao Kai Hsu, Der Yuan Chen, Chin San Liu, Ching Yuang Lin, Nahoko Kaniwa, Yoshiro Saito, Yukitoshi Takahashi, Ryosuke Nakamura, Hiroaki Azukizawa, Yongyong Shi, Tzu Hao Wang, Shiow Shuh Chuang, Shih Feng Tsai, Chee Jen Chang, Yu Sun Chang, Shuen Iu Hung

Chang Gung Memorial Hospital
Chang Gung University
National Yang Ming Chiao Tung University
Ming Chuan University
Taipei Medical University
Hospital Sultanah Aminah
National Cheng Kung University
Veterans General Hospital-Taichung Taiwan
Changhua Christian Hospital
China Medical University Taichung
National Institute of Health Sciences Tokyo
National Hospital Organization Shizuoka Institute of Epilepsy and Neurological Disorders
The University of Osaka
Shanghai Genome Pilot Institutes for Genomics and Human Health
National Health Research Institutes Taiwan

Research output: Contribution to journal › Article › peer-review

286 Scopus citations

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. Ameta-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.

Original language	English
Pages (from-to)	525-535
Number of pages	11
Journal	JAMA
Volume	312
Issue number	5
DOIs	https://doi.org/10.1001/jama.2014.7859
State	Published - 6 Aug 2014
Externally published	Yes

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10.1001/jama.2014.7859

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Chung, W. H., Chang, W. C., Lee, Y. S., Wu, Y. Y., Yang, C. H., Ho, H. C., Chen, M. J., Lin, J. Y., Hui, R. C. Y., Ho, J. C., Wu, W. M., Chen, T. J., Wu, T., Wu, Y. R., Hsih, M. S., Tu, P. H., Chang, C. N., Hsu, C. N., Wu, T. L., ... Hung, S. I. (2014). Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA, 312(5), 525-535. https://doi.org/10.1001/jama.2014.7859

@article{72f85e5d0e6f42118c2ca32770607856,

title = "Genetic variants associated with phenytoin-related severe cutaneous adverse reactions",

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. Ameta-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.",

author = "Chung, \{Wen Hung\} and Chang, \{Wan Chun\} and Lee, \{Yun Shien\} and Wu, \{Ying Ying\} and Yang, \{Chih Hsun\} and Ho, \{Hsin Chun\} and Chen, \{Ming Jing\} and Lin, \{Jing Yi\} and Hui, \{Rosaline Chung Yee\} and Ho, \{Ji Chen\} and Wu, \{Wei Ming\} and Chen, \{Ting Jui\} and Tony Wu and Wu, \{Yih Ru\} and Hsih, \{Mo Song\} and Tu, \{Po Hsun\} and Chang, \{Chen Nen\} and Hsu, \{Chien Ning\} and Wu, \{Tsu Lan\} and Choon, \{Siew Eng\} and Hsu, \{Chao Kai\} and Chen, \{Der Yuan\} and Liu, \{Chin San\} and Lin, \{Ching Yuang\} and Nahoko Kaniwa and Yoshiro Saito and Yukitoshi Takahashi and Ryosuke Nakamura and Hiroaki Azukizawa and Yongyong Shi and Wang, \{Tzu Hao\} and Chuang, \{Shiow Shuh\} and Tsai, \{Shih Feng\} and Chang, \{Chee Jen\} and Chang, \{Yu Sun\} and Hung, \{Shuen Iu\}",

year = "2014",

month = aug,

day = "6",

doi = "10.1001/jama.2014.7859",

language = "英語",

volume = "312",

pages = "525--535",

journal = "JAMA",

issn = "0098-7484",

publisher = "American Medical Association",

number = "5",

}

Chung, WH, Chang, WC, Lee, YS, Wu, YY, Yang, CH, Ho, HC, Chen, MJ, Lin, JY, Hui, RCY, Ho, JC, Wu, WM, Chen, TJ, Wu, T, Wu, YR, Hsih, MS, Tu, PH, Chang, CN, Hsu, CN, Wu, TL, Choon, SE, Hsu, CK, Chen, DY, Liu, CS, Lin, CY, Kaniwa, N, Saito, Y, Takahashi, Y, Nakamura, R, Azukizawa, H, Shi, Y, Wang, TH, Chuang, SS, Tsai, SF, Chang, CJ, Chang, YS & Hung, SI 2014, 'Genetic variants associated with phenytoin-related severe cutaneous adverse reactions', JAMA, vol. 312, no. 5, pp. 525-535. https://doi.org/10.1001/jama.2014.7859

TY - JOUR

T1 - Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

AU - Chung, Wen Hung

AU - Chang, Wan Chun

AU - Lee, Yun Shien

AU - Wu, Ying Ying

AU - Yang, Chih Hsun

AU - Ho, Hsin Chun

AU - Chen, Ming Jing

AU - Lin, Jing Yi

AU - Hui, Rosaline Chung Yee

AU - Ho, Ji Chen

AU - Wu, Wei Ming

AU - Chen, Ting Jui

AU - Wu, Tony

AU - Wu, Yih Ru

AU - Hsih, Mo Song

AU - Tu, Po Hsun

AU - Chang, Chen Nen

AU - Hsu, Chien Ning

AU - Wu, Tsu Lan

AU - Choon, Siew Eng

AU - Hsu, Chao Kai

AU - Chen, Der Yuan

AU - Liu, Chin San

AU - Lin, Ching Yuang

AU - Kaniwa, Nahoko

AU - Saito, Yoshiro

AU - Takahashi, Yukitoshi

AU - Nakamura, Ryosuke

AU - Azukizawa, Hiroaki

AU - Shi, Yongyong

AU - Wang, Tzu Hao

AU - Chuang, Shiow Shuh

AU - Tsai, Shih Feng

AU - Chang, Chee Jen

AU - Chang, Yu Sun

AU - Hung, Shuen Iu

PY - 2014/8/6

Y1 - 2014/8/6

N2 - 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. Ameta-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.

AB - 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. Ameta-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.

UR - https://www.scopus.com/pages/publications/84905901610

U2 - 10.1001/jama.2014.7859

DO - 10.1001/jama.2014.7859

M3 - 記事

C2 - 25096692

AN - SCOPUS:84905901610

SN - 0098-7484

VL - 312

SP - 525

EP - 535

JO - JAMA

JF - JAMA

IS - 5

ER -

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

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