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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/8222


    Title: Genetic variants associated with phenytoin-related severe cutaneous adverse reactions
    Authors: 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, YY;Wang, TH;Chuang, SS;Tsai, SF;Chang, CJ;Chang, YS;Hung, SI;Taiwan Severe Cutaneous Adverse Reaction Consortium;Japan PharmacogenomicsData Science Consortium
    Contributors: Institute of Molecular and Genomic Medicine
    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 x 10-1). 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.
    Date: 2014-08
    Relation: JAMA. 2014 Aug;312(5):525-534.
    Link to: http://dx.doi.org/10.1001/jama.2014.7859
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0098-7484&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000339808600021
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84905901610
    Appears in Collections:[蔡世峯] 期刊論文

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