HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians

Shih Chi Su; Chun Bing Chen; Wan Chun Chang; Chuang Wei Wang; Wen Lang Fan; Lai Ying Lu; Ryosuke Nakamura; Yoshiro Saito; Mayumi Ueta; Shigeru Kinoshita; Chonlaphat Sukasem; Kittika Yampayon; Pornpimol Kijsanayotin; Nontaya Nakkam; Niwat Saksit; Wichittra Tassaneeyakul; Michiko Aihara; Yu Jr Lin; Chee Jen Chang; Tony Wu; Shuen Iu Hung; Wen Hung Chung

doi:10.1002/cpt.1190

HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians

Shih Chi Su, Chun Bing Chen, Wan Chun Chang, Chuang Wei Wang, Wen Lang Fan, Lai Ying Lu, Ryosuke Nakamura, Yoshiro Saito, Mayumi Ueta, Shigeru Kinoshita, Chonlaphat Sukasem, Kittika Yampayon, Pornpimol Kijsanayotin, Nontaya Nakkam, Niwat Saksit, Wichittra Tassaneeyakul, Michiko Aihara, Yu Jr Lin, Chee Jen Chang, Tony WuShuen Iu Hung^*, Wen Hung Chung

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

64 Scopus citations

Abstract

To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

Original language	English
Pages (from-to)	476-485
Number of pages	10
Journal	Clinical Pharmacology and Therapeutics
Volume	105
Issue number	2
DOIs	https://doi.org/10.1002/cpt.1190
State	Published - 02 2019

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© 2018 American Society for Clinical Pharmacology and Therapeutics

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Su, S. C., Chen, C. B., Chang, W. C., Wang, C. W., Fan, W. L., Lu, L. Y., Nakamura, R., Saito, Y., Ueta, M., Kinoshita, S., Sukasem, C., Yampayon, K., Kijsanayotin, P., Nakkam, N., Saksit, N., Tassaneeyakul, W., Aihara, M., Lin, Y. J., Chang, C. J., ... Chung, W. H. (2019). HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians. Clinical Pharmacology and Therapeutics, 105(2), 476-485. https://doi.org/10.1002/cpt.1190

@article{78f39371383e4fb3b26b38cd17d309f8,

title = "HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians",

abstract = "To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.",

author = "Su, {Shih Chi} and Chen, {Chun Bing} and Chang, {Wan Chun} and Wang, {Chuang Wei} and Fan, {Wen Lang} and Lu, {Lai Ying} and Ryosuke Nakamura and Yoshiro Saito and Mayumi Ueta and Shigeru Kinoshita and Chonlaphat Sukasem and Kittika Yampayon and Pornpimol Kijsanayotin and Nontaya Nakkam and Niwat Saksit and Wichittra Tassaneeyakul and Michiko Aihara and Lin, {Yu Jr} and Chang, {Chee Jen} and Tony Wu and Hung, {Shuen Iu} and Chung, {Wen Hung}",

note = "Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Pharmacology and Therapeutics",

year = "2019",

month = feb,

doi = "10.1002/cpt.1190",

language = "英语",

volume = "105",

pages = "476--485",

journal = "Clinical Pharmacology and Therapeutics",

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Su, SC, Chen, CB, Chang, WC, Wang, CW, Fan, WL, Lu, LY, Nakamura, R, Saito, Y, Ueta, M, Kinoshita, S, Sukasem, C, Yampayon, K, Kijsanayotin, P, Nakkam, N, Saksit, N, Tassaneeyakul, W, Aihara, M, Lin, YJ, Chang, CJ, Wu, T, Hung, SI & Chung, WH 2019, 'HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians', Clinical Pharmacology and Therapeutics, vol. 105, no. 2, pp. 476-485. https://doi.org/10.1002/cpt.1190

TY - JOUR

T1 - HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians

AU - Su, Shih Chi

AU - Chen, Chun Bing

AU - Chang, Wan Chun

AU - Wang, Chuang Wei

AU - Fan, Wen Lang

AU - Lu, Lai Ying

AU - Nakamura, Ryosuke

AU - Saito, Yoshiro

AU - Ueta, Mayumi

AU - Kinoshita, Shigeru

AU - Sukasem, Chonlaphat

AU - Yampayon, Kittika

AU - Kijsanayotin, Pornpimol

AU - Nakkam, Nontaya

AU - Saksit, Niwat

AU - Tassaneeyakul, Wichittra

AU - Aihara, Michiko

AU - Lin, Yu Jr

AU - Chang, Chee Jen

AU - Wu, Tony

AU - Hung, Shuen Iu

AU - Chung, Wen Hung

PY - 2019/2

Y1 - 2019/2

N2 - To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

AB - To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

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DO - 10.1002/cpt.1190

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AN - SCOPUS:85054192749

SN - 0009-9236

VL - 105

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JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 2

ER -

HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians

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