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

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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 - 2006 Apr 1

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hung, S. I., Chung, W. H., Jee, S. H., Chen, W. C., Chang, Y. T., Lee, W. R., Hu, S. L., Wu, M. T., Chen, G. S., Wong, T. W., Hsiao, P. F., Chen, W. H., Shih, H. Y., Fang, W. H., Wei, C. Y., Lou, Y. H., Huang, Y. L., Lin, J. J., & Chen, Y. T. (2006). Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenetics and Genomics, 16(4), 297-306. https://doi.org/10.1097/01.fpc.0000199500.46842.4a