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

Yi-Wu Shi, Fu-Li Min, Dong Zhou, Bin Qin, Juan Wang, Fa-Yun Hu, Ying-Kit Cheung, Jin-Hua Zhou, Xiang-Shu Hu, Jue-Qian Zhou, Lie-Min Zhou, Zhong-Zheng Zheng, Jie Pan, Na He, Zhi-Sheng Liu, Yun-Qi Hou, Kheng-Seang Lim, Yang-Mei Ou, Amy Hui-Ping Khor, Ching-Ching Ng, Bi-Jun Mao, Xiao-Rong Liu, Bing-Mei Li, Yao-Yun Kuan, Yong-Hong Yi, Xue-Lian He, Xiao-Yan Deng, Tao Su, Patrick Kwan, Wei-Ping Liao, Yi-Wu Shi, Fu-Li Min, Dong Zhou, Bin Qin, Juan Wang, Fa-Yun Hu, Ying-Kit Cheung, Jin-Hua Zhou, Xiang-Shu Hu, Jue-Qian Zhou, Lie-Min Zhou, Zhong-Zheng Zheng, Jie Pan, Na He, Zhi-Sheng Liu, Yun-Qi Hou, Kheng-Seang Lim, Yang-Mei Ou, Amy Hui-Ping Khor, Ching-Ching Ng, Bi-Jun Mao, Xiao-Rong Liu, Bing-Mei Li, Yao-Yun Kuan, Yong-Hong Yi, Xue-Lian He, Xiao-Yan Deng, Tao Su, Patrick Kwan, Wei-Ping Liao

Abstract

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.

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Presence of HLA-B*15:02 and HLA-A*24:02…
Figure 1. Presence of HLA-B*15:02 and HLA-A*24:02 alleles in CBZ- (A), LTG- (B), and PHT- (C) induced SJS/TEN
CBZ = carbamazepine; HLA = human leukocyte antigen; LTG = lamotrigine; PHT = phenytoin; SJS/TEN = Stevens-Johnson syndrome/toxic epidermal necrolysis.
Figure 2. Distribution of HLA-A*24:02 allele across…
Figure 2. Distribution of HLA-A*24:02 allele across the phenotypes of cADRs induced by aromatic AEDs
Data were from 14 studies, including 7 that used drug-tolerant controls, 5 that used population controls, and 2 that used both types of controls, including populations from Japan, Korea, Malaysia, Mexico, Norway, and China (e-supplement). Data from tolerant controls (A) and population controls (B) were analyzed separately. The phenotypes of cADRs included SJS/TEN, MPE, and unspecified cADRs, according to the descriptions in the original reports. I2 and τ2 and represent measures of heterogeneity. Study weighting (indicated by different sizes of squares) refers to the proportion of participants who were recruited from each study. Horizontal lines represent 95% CIs; diamonds indicate pooled ORs. AED = antiepileptic drug; cADRs = cutaneous adverse drug reactions; CBZ = carbamazepine; CI = confidence interval; HLA = human leukocyte antigen; LTG = lamotrigine; MPE = maculopapular exanthema; OR = odds ratio; PHT = phenytoin; SJS/TEN = Stevens-Johnson syndrome/toxic epidermal necrolysis.

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Source: PubMed

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