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, 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 Choon, Chao-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
Journal: JAMA (2014)

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.