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 language | English |
|---|---|
| Pages (from-to) | 297-306 |
| Number of pages | 10 |
| Journal | Pharmacogenetics and Genomics |
| Volume | 16 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2006 |
Fingerprint
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 journal › Article
}
TY - JOUR
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
Y1 - 2006/4
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.
AB - 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.
KW - Carbamazepine
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
UR - http://www.scopus.com/inward/record.url?scp=33645082244&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645082244&partnerID=8YFLogxK
U2 - 10.1097/01.fpc.0000199500.46842.4a
DO - 10.1097/01.fpc.0000199500.46842.4a
M3 - Article
C2 - 16538176
AN - SCOPUS:33645082244
VL - 16
SP - 297
EP - 306
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 4
ER -