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Original Investigation |

Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

Wen-Hung Chung, MD, PhD1,2,3; Wan-Chun Chang, MS4; Yun-Shien Lee, PhD5; Ying-Ying Wu, MS4; Chih-Hsun Yang, MD2,3; Hsin-Chun Ho, MD1,3; Ming-Jing Chen, MD2,3; Jing-Yi Lin, MD1,3; Rosaline Chung-Yee Hui, MD, PhD2,3; Ji-Chen Ho, MD3,6; Wei-Ming Wu, MD, PhD3,6; Ting-Jui Chen, MD4,7; Tony Wu, MD, PhD3,8; Yih-Ru Wu, MD, PhD3,8; Mo-Song Hsih, MD3,8; Po-Hsun Tu, MD3,9; Chen-Nen Chang, MD, PhD3,9; Chien-Ning Hsu, PhD3,10; Tsu-Lan Wu, PhD3,11; Siew-Eng Choon, MD12; Chao-Kai Hsu, MD, PhD13; Der-Yuan Chen, MD, PhD14; Chin-San Liu, MD, PhD15; Ching-Yuang Lin, MD, PhD16; Nahoko Kaniwa, PhD17; Yoshiro Saito, PhD17; Yukitoshi Takahashi, MD, PhD18; Ryosuke Nakamura, PhD17; Hiroaki Azukizawa, MD, PhD19; Yongyong Shi, PhD20; Tzu-Hao Wang, MD, PhD3,21,22; Shiow-Shuh Chuang, MD, PhD3,23; Shih-Feng Tsai, MD, PhD24; Chee-Jen Chang, PhD3,25; Yu-Sun Chang, PhD26; Shuen-Iu Hung, PhD4; for the Taiwan Severe Cutaneous Adverse Reaction Consortium and the Japan Pharmacogenomics Data Science Consortium
[+] Author Affiliations
1Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan
2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan
3College of Medicine, Chang Gung University, Taoyuan, Taiwan
4Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
5Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan
6Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
7Department of Dermatology, Taipei Medical University–Wan Fang Hospital, Taipei, Taiwan
8Department of Neurology, Chang Gung Memorial Hospital, Linkou, Taiwan
9Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan
10Department of Pharmacy, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
11Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
12Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Johor, Malaysia
13Department of Dermatology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan
14Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
15Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
16Department of Pediatrics, China Medicine University, Taichung, Taiwan
17Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan
18Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
19Department of Dermatology, Course of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan
20Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China
21Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou, Taiwan
22Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
23Department of Plastic Surgery and Burn Center, Chang Gung Memorial Hospital, Linkou, Taiwan
24Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
25Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan
26Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
JAMA. 2014;312(5):525-534. doi:10.1001/jama.2014.7859.
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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 × 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 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.

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Figure 1.
Genome-Wide Association Scan and Linkage Disequilibrium Map for the CYP2C Region Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

A, Manhattan plot showing associations between CYP2C single-nucleotide polymorphisms (SNPs) and phenytoin-related severe cutaneous adverse reactions. Each dot represents a −log10P value calculated by Fisher exact test for the allele frequency in 60 severe cutaneous adverse reaction cases and 412 population controls. The red horizontal line represents P = 5.9 × 10−8, indicating P = .05 by Bonferroni correction for the multiple comparisons (0.05/854 035). B, The −log10P values of SNPs on the chromosome 10q23.33 (physical position: 96.0-97.5 Mb) and the linkage disequilibrium heat map based on pairwise D′ values from genome-wide association study data from 412 controls. The genomic coordinates are based on the NCBI Human Genome build 37.5, and the standard ideogram of chromosome 10 was taken from the NCBI Human Genome resource site. Top, Single-nucleotide polymorphisms with P≤.01 are indicated by blue and P>.01 by cyan. The physical position between chromosome 10 (96.4-97.0 Mb), which spans CYP2C18, CYP2C19, CYP2C9, CYP2C8, and C10orf129 genes, is indicated by pink lines. Bottom, Black triangles mark the linkage disequilibrium blocks. A D′ value of 1 indicates that the examined loci exhibit complete dependency while a value of 0 demonstrates the independence of one another. The colors represent the D′ values: red (0.5≤D′ values ≤1), white to pink (0<D′ values <0.5), purple (D′ = 0).

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Figure 2.
Linkage Disequilibrium Heat Maps for the CYP2C Region Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

The linkage disequilibrium heat maps are drawn based on pairwise D′ values of the 10 risk single-nucleotide polymorphisms using the data of 412 controls (A) and 90 cases of phenytoin-related severe cutaneous adverse reactions (B).

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Figure 3.
Distribution of the CYP2C9*3 Variant in Cases With Phenytoin-Related Severe Cutaneous Adverse Reactions and Population Controls

Patients with phenytoin-related severe cutaneous adverse reactions were recruited at the Chang Gung Memorial Hospital health system and the Taiwan Severe Cutaneous Adverse Reaction Consortium in Taiwan, Hospital Sultanah Aminah Johor Bahru in Malaysia, and centers collaborating with the National Institute of Health Sciences and Osaka University in Japan. Study weighting (indicated by size of data markers) refers to the proportion of participants who were recruited from each study. The τ2 and I2 represent measures of heterogeneity. Diamonds represent pooled odds ratios (Mantel-Haenszel method, random effects) and error bars indicate 95% CIs. DRESS indicates drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

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