Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.
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*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, 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=2.2x10, 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.
Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road Section 2, Nankang, Taipei, Taiwan.
Shuen-Iu
SI
Hung
Wen-Hung
WH
Chung
Shiou-Hwa
SH
Jee
Wen-Chieh
WC
Chen
Yun-Ting
YT
Chang
Woan-Ruoh
WR
Lee
Shu-Ling
SL
Hu
Meng-Tse
MT
Wu
Gwo-Shing
GS
Chen
Tak-Wah
TW
Wong
Pa-Fan
PF
Hsiao
Wei-Hsuan
WH
Chen
Han-Yu
HY
Shih
Wu-Hsiang
WH
Fang
Chun-Yu
CY
Wei
Yi-Hui
YH
Lou
Yau-Li
YL
Huang
Juei-Jueng
JJ
Lin
Yuan-Tsong
YT
Chen
D000927:Anticonvulsants / Q000009:adverse effects*; D002220:Carbamazepine / Q000009:adverse effects*; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics*; D005076:Exanthema / Q000473:pathology; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology
D000927:Anticonvulsants; D015235:HLA-B Antigens; D002220:Carbamazepine