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 ChoonChao 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

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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 languageEnglish
Pages (from-to)525-535
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume312
Issue number5
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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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 - Journal of the American Medical Association, 312(5), 525-535. https://doi.org/10.1001/jama.2014.7859