Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions

Shuen Iu Hung, Wen Hung Chung, Shiou Hwa Jee, Wen Chieh Chen, Yun Ting Chang, Woan Ruoh Lee, Shu Ling Hu, Meng Tse Wu, Gwo Shing Chen, Tak Wah Wong, Pa Fan Hsiao, Wei Hsuan Chen, Han Yu Shih, Wu Hsiang Fang, Chun Yu Wei, Yi Hui Lou, Yau Li Huang, Juei Jueng Lin, Yuan Tsong Chen

Research output: Contribution to journalArticle

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Abstract

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc = 1.6 × 10-41, odds ratio (OR) = 1357; 95% confidence interval (CI) = 193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc = 2.2 × 10-3, OR = 17.5; 95% CI = 4.6-66.5), and HSS with SNPs in the motilin gene (Pc = 0.0064, OR = 7.11; 95% CI = 3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

Original languageEnglish
Pages (from-to)297-306
Number of pages10
JournalPharmacogenetics and Genomics
Volume16
Issue number4
DOIs
Publication statusPublished - Apr 2006

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Carbamazepine
Genetic Predisposition to Disease
Drug-Related Side Effects and Adverse Reactions
Stevens-Johnson Syndrome
Skin
HLA-B Antigens
Single Nucleotide Polymorphism
Hypersensitivity
Major Histocompatibility Complex
Odds Ratio
Confidence Intervals
Genes
Motilin
Epoxide Hydrolases
Cytochrome P-450 CYP3A
Histocompatibility Testing
MHC Class II Genes
HLA-A Antigens
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Heat-Shock Proteins

Keywords

  • Carbamazepine
  • Cutaneous adverse drug reactions
  • Genetic polymorphisms
  • Hypersensitivity syndrome
  • Major histocompatibility complex
  • Pharmacogenomics
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. / Hung, Shuen Iu; Chung, Wen Hung; Jee, Shiou Hwa; Chen, Wen Chieh; Chang, Yun Ting; Lee, Woan Ruoh; Hu, Shu Ling; Wu, Meng Tse; Chen, Gwo Shing; Wong, Tak Wah; Hsiao, Pa Fan; Chen, Wei Hsuan; Shih, Han Yu; Fang, Wu Hsiang; Wei, Chun Yu; Lou, Yi Hui; Huang, Yau Li; Lin, Juei Jueng; Chen, Yuan Tsong.

In: Pharmacogenetics and Genomics, Vol. 16, No. 4, 04.2006, p. 297-306.

Research output: Contribution to journalArticle

Hung, SI, Chung, WH, Jee, SH, Chen, WC, Chang, YT, Lee, WR, Hu, SL, Wu, MT, Chen, GS, Wong, TW, Hsiao, PF, Chen, WH, Shih, HY, Fang, WH, Wei, CY, Lou, YH, Huang, YL, Lin, JJ & Chen, YT 2006, 'Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions', Pharmacogenetics and Genomics, vol. 16, no. 4, pp. 297-306. https://doi.org/10.1097/01.fpc.0000199500.46842.4a
Hung, Shuen Iu ; Chung, Wen Hung ; Jee, Shiou Hwa ; Chen, Wen Chieh ; Chang, Yun Ting ; Lee, Woan Ruoh ; Hu, Shu Ling ; Wu, Meng Tse ; Chen, Gwo Shing ; Wong, Tak Wah ; Hsiao, Pa Fan ; Chen, Wei Hsuan ; Shih, Han Yu ; Fang, Wu Hsiang ; Wei, Chun Yu ; Lou, Yi Hui ; Huang, Yau Li ; Lin, Juei Jueng ; Chen, Yuan Tsong. / Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 4. pp. 297-306.
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T1 - Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions

AU - Hung, Shuen Iu

AU - Chung, Wen Hung

AU - Jee, Shiou Hwa

AU - Chen, Wen Chieh

AU - Chang, Yun Ting

AU - Lee, Woan Ruoh

AU - Hu, Shu Ling

AU - Wu, Meng Tse

AU - Chen, Gwo Shing

AU - Wong, Tak Wah

AU - Hsiao, Pa Fan

AU - Chen, Wei Hsuan

AU - Shih, Han Yu

AU - Fang, Wu Hsiang

AU - Wei, Chun Yu

AU - Lou, Yi Hui

AU - Huang, Yau Li

AU - Lin, Juei Jueng

AU - Chen, Yuan Tsong

PY - 2006/4

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N2 - The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc = 1.6 × 10-41, odds ratio (OR) = 1357; 95% confidence interval (CI) = 193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc = 2.2 × 10-3, OR = 17.5; 95% CI = 4.6-66.5), and HSS with SNPs in the motilin gene (Pc = 0.0064, OR = 7.11; 95% CI = 3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

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KW - Cutaneous adverse drug reactions

KW - Genetic polymorphisms

KW - Hypersensitivity syndrome

KW - Major histocompatibility complex

KW - Pharmacogenomics

KW - Stevens-Johnson syndrome

KW - Toxic epidermal necrolysis

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