HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema

Yi Wu Shi, Jie Wang, Fu Li Min, Wen Jun Bian, Bi Jun Mao, Yong Mao, Bing Qin, Bing Mei Li, Yang Mei Ou, Yun Qi Hou, Xin Zou, Bao Zhu Guan, Na He, Yong Jun Chen, Xue Lian Li, Juan Wang, Wei Yi Deng, Han Kui Liu, Nan Xiang Shen, Xiao Rong LiuYong Hong Yi, Lie Min Zhou, Dong Zhou, Patrick Kwan, Wei Ping Liao

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To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, pc = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

Original languageEnglish
Article number671572
Number of pages10
JournalFrontiers in Pharmacology
Publication statusPublished - 26 May 2021


  • antiepileptic drugs
  • human leukocyte antigen
  • maculopapular exanthema
  • oxcarbazepine
  • risk factor

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