title: Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: 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.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan.
authors.forename: Yun-Shien
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Chun
authors.initials: HC
authors.lastname: Ho
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Jing
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Rosaline Chung-Yee
authors.initials: RC
authors.lastname: Hui
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Ji-Chen
authors.initials: JC
authors.lastname: Ho
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan7Department of Dermatology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Ting-Jui
authors.initials: TJ
authors.lastname: Chen
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Tony
authors.initials: T
authors.lastname: Wu
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Mo-Song
authors.initials: MS
authors.lastname: Hsih
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Tu
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Chen-Nen
authors.initials: CN
authors.lastname: Chang
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan10Department of Pharmacy, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Hsu
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan11Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Tsu-Lan
authors.initials: TL
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Johor, Malaysia.
authors.forename: Siew-Eng
authors.initials: SE
authors.lastname: Choon
authors.affiliation: Department of Dermatology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Hsu
authors.affiliation: Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chin-San
authors.initials: CS
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, China Medicine University, Taichung, Taiwan.
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Dermatology, Course of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Azukizawa
authors.affiliation: Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan23Department of Plastic Surgery and Burn Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Shiow-Shuh
authors.initials: SS
authors.lastname: Chuang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Tsai
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan25Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Chee-Jen
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004802:Eosinophilia / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010672:Phenytoin / Q000009:adverse effects* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D013262:Stevens-Johnson Syndrome / Q000235:genetics*; D013624:Taiwan; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases