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, 2136, 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 [P-c = 1.6 x 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: MIRE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (P-c = 2.2 x 10(-3), OR=17.5; 95% CI = 4.6-66.5), and HSS with SNPs in the motilin gene (P-c = 0.0064, OR = 7.11; 95% CI =3.1-16.5) located terminal to the MHC class 11 genes. No SNIPS 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 genetic susceptibility to CBZ-induced cADRs is phenotypespecific.