DataSheet2_HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema.PDF (81.08 kB)
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DataSheet2_HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema.PDF

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posted on 26.05.2021, 05:25 by 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 Liu, Yong-Hong Yi, Lie-Min Zhou, Dong Zhou, Patrick Kwan, Wei-Ping Liao

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.