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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| Vydané v: | JAMA : the journal of the American Medical Association Ročník 312; číslo 5; s. 525 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
06.08.2014
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| ISSN: | 1538-3598, 1538-3598 |
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| Abstract | 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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| AbstractList | 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.IMPORTANCEThe 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.OBJECTIVETo 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.DESIGN, SETTING, AND PARTICIPANTSCase-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.MAIN OUTCOMES AND MEASURESSpecific 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.RESULTSThe 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.CONCLUSIONS AND RELEVANCEThis study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors 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 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. |
| Author | Wu, Wei-Ming Tu, Po-Hsun Ho, Hsin-Chun Wu, Yih-Ru Chen, Ming-Jing Ho, Ji-Chen Chen, Der-Yuan Lee, Yun-Shien Azukizawa, Hiroaki Chung, Wen-Hung Choon, Siew-Eng Shi, Yongyong Wang, Tzu-Hao Hui, Rosaline Chung-Yee Chang, Yu-Sun Hung, Shuen-Iu Chang, Chee-Jen Chen, Ting-Jui Lin, Ching-Yuang Saito, Yoshiro Hsih, Mo-Song Kaniwa, Nahoko Tsai, Shih-Feng Yang, Chih-Hsun Wu, Tony Chang, Chen-Nen Chuang, Shiow-Shuh Nakamura, Ryosuke Hsu, Chien-Ning Wu, Tsu-Lan Chang, Wan-Chun Wu, Ying-Ying Liu, Chin-San Lin, Jing-Yi Takahashi, Yukitoshi Hsu, Chao-Kai |
| Author_xml | – sequence: 1 givenname: Wen-Hung surname: Chung fullname: Chung, Wen-Hung organization: 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 – sequence: 2 givenname: Wan-Chun surname: Chang fullname: Chang, Wan-Chun organization: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan – sequence: 3 givenname: Yun-Shien surname: Lee fullname: Lee, Yun-Shien organization: Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan – sequence: 4 givenname: Ying-Ying surname: Wu fullname: Wu, Ying-Ying organization: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan – sequence: 5 givenname: Chih-Hsun surname: Yang fullname: Yang, Chih-Hsun organization: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 6 givenname: Hsin-Chun surname: Ho fullname: Ho, Hsin-Chun organization: Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 7 givenname: Ming-Jing surname: Chen fullname: Chen, Ming-Jing organization: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 8 givenname: Jing-Yi surname: Lin fullname: Lin, Jing-Yi organization: Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 9 givenname: Rosaline Chung-Yee surname: Hui fullname: Hui, Rosaline Chung-Yee organization: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan3College of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 10 givenname: Ji-Chen surname: Ho fullname: Ho, Ji-Chen organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan – sequence: 11 givenname: Wei-Ming surname: Wu fullname: Wu, Wei-Ming organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan – sequence: 12 givenname: Ting-Jui surname: Chen fullname: Chen, Ting-Jui organization: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan7Department of Dermatology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan – sequence: 13 givenname: Tony surname: Wu fullname: Wu, Tony organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 14 givenname: Yih-Ru surname: Wu fullname: Wu, Yih-Ru organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 15 givenname: Mo-Song surname: Hsih fullname: Hsih, Mo-Song organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 16 givenname: Po-Hsun surname: Tu fullname: Tu, Po-Hsun organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 17 givenname: Chen-Nen surname: Chang fullname: Chang, Chen-Nen organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 18 givenname: Chien-Ning surname: Hsu fullname: Hsu, Chien-Ning organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan10Department of Pharmacy, Chang Gung Memorial Hospital, Kaohsiung, Taiwan – sequence: 19 givenname: Tsu-Lan surname: Wu fullname: Wu, Tsu-Lan organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan11Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 20 givenname: Siew-Eng surname: Choon fullname: Choon, Siew-Eng organization: Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Johor, Malaysia – sequence: 21 givenname: Chao-Kai surname: Hsu fullname: Hsu, Chao-Kai organization: Department of Dermatology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan – sequence: 22 givenname: Der-Yuan surname: Chen fullname: Chen, Der-Yuan organization: Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan – sequence: 23 givenname: Chin-San surname: Liu fullname: Liu, Chin-San organization: Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan – sequence: 24 givenname: Ching-Yuang surname: Lin fullname: Lin, Ching-Yuang organization: Department of Pediatrics, China Medicine University, Taichung, Taiwan – sequence: 25 givenname: Nahoko surname: Kaniwa fullname: Kaniwa, Nahoko organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 26 givenname: Yoshiro surname: Saito fullname: Saito, Yoshiro organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 27 givenname: Yukitoshi surname: Takahashi fullname: Takahashi, Yukitoshi organization: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan – sequence: 28 givenname: Ryosuke surname: Nakamura fullname: Nakamura, Ryosuke organization: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan – sequence: 29 givenname: Hiroaki surname: Azukizawa fullname: Azukizawa, Hiroaki organization: Department of Dermatology, Course of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan – sequence: 30 givenname: Yongyong surname: Shi fullname: Shi, Yongyong organization: Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China – sequence: 31 givenname: Tzu-Hao surname: Wang fullname: Wang, Tzu-Hao organization: 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 – sequence: 32 givenname: Shiow-Shuh surname: Chuang fullname: Chuang, Shiow-Shuh organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan23Department of Plastic Surgery and Burn Center, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 33 givenname: Shih-Feng surname: Tsai fullname: Tsai, Shih-Feng organization: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan – sequence: 34 givenname: Chee-Jen surname: Chang fullname: Chang, Chee-Jen organization: College of Medicine, Chang Gung University, Taoyuan, Taiwan25Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan – sequence: 35 givenname: Yu-Sun surname: Chang fullname: Chang, Yu-Sun organization: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan – sequence: 36 givenname: Shuen-Iu surname: Hung fullname: Hung, Shuen-Iu organization: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25096692$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Genetic variants associated with phenytoin-related severe cutaneous adverse reactions |
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