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- Title
Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions.
- Authors
Wen-Hung Chung; Wan-Chun Chang; Yun-Shien Lee; Ying-Ying Wu; Chih-Hsun Yang; Hsin-Chun Ho; Ming-Jing Chen; Jing-Yi Lin; Chung-Yee Hui, Rosaline; Ji-Chen Ho; Wei-Ming Wu; Ting-Jui Chen; Wu, Tony; Yih-Ru Wu; Mo-Song Hsih; Po-Hsun Tu; Chen-Nen Chang; Chien-Ning Hsu; Tsu-Lan Wu; Siew-Eng Choon
- 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% Cl, 6.6-20; P=1.1 x 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% Cl, 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.
- Subjects
ANTICONVULSANTS; PHENYTOIN; DRUG side effects; PHARMACODYNAMICS; EOSINOPHILIA; GENETICS
- Publication
JAMA: Journal of the American Medical Association, 2014, Vol 312, Issue 5, p525
- ISSN
0098-7484
- Publication type
Article
- DOI
10.1001/jama.2014.7859