HLA-A∗24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions

Objective: To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug-induced cutaneous adverse reactions. Methods: A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug-induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes. Results: HLA-B∗15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10^-15). In addition, HLA-A∗24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10^-5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B∗15:02 and HLA-A∗24:02. Positivity for HLA-A∗24:02 and/or HLA-B∗15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A∗24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association. Conclusions: HLA-A∗24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.