HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis

Abstract

HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update

“…Other less frequently carried members of the HLA‐B75 serotype include HLA‐B*15:08, HLA‐B*15:11 , and HLA‐B*15:21 . The HLA proteins coded by these alleles share structural similarity and peptide binding grooves, and hence peptide binding specificities, with HLA‐B*15:02 and have also been reported in association with carbamazepine‐induced SJS/TEN . Currently, the majority of available data focuses on the risk of carbamazepine‐induced SJS/TEN conferred by the presence of HLA‐B*15:02 and is the basis for the design of efficient single allele molecular typing assays.…”

“…The HLA proteins coded by these alleles share structural similarity and peptide binding grooves, and hence peptide binding specificities, with HLA-B*15:02 and have also been reported in association with carbamazepine-induced SJS/TEN. 26,[36][37][38] Currently, the majority of available data focuses on the risk of carbamazepine-induced SJS/TEN conferred by the presence of HLA-B*15:02 and is the basis for the design of efficient single allele molecular typing assays. However, some labs may provide high-resolution HLA-B typing and the possibility of carbamazepine-induced SJS/TEN with HLA-B*15:08, HLA-B*15:11, HLA-B*15:21, and even less common HLA-B75 serotype alleles such as HLA-B*15:30 and HLA-B*15:31 where carbamazepine-induced SJS/TEN has yet to be described, needs to be considered a potential risk if this information is available.…”

Cost‐effectiveness of screening for HLA‐B*1502 prior to initiation of carbamazepine in epilepsy patients of Asian ancestry in the United States

“…Occurring with lower frequencies than HLA-B*1502 in various Asian ethnic groups, these other HLA alleles have also been associated with SJS/TEN. 8,10,12,44,45 HLA-B75 serotype members share the 63rd arginine residue, which is reportedly important for formation of a drug-HLA molecule complex found to induce an in vitro lymphocyte cytotoxic response to carbamazepine. 46 There are some limitations of this study.…”

Association between HLA alleles and lamotrigine-induced cutaneous adverse drug reactions in Asian populations: A meta-analysis

“…HLA-A*2402 belonging to MHC class I genes in the meta-analysis is also found to be associated with LTG-induced MPE, indicating the pathogenesis remains unclear. In recent years, in silico analysis was applied and indicated the details of the molecular behavior of HLA-B alleles in the pathogenesis of SJS/TEN; the evidence of significant association was found between CBZ-induced SJS and HLA-B75 molecules [24]. Moreover, the specific HLA class II haplotypes were found to be protective alleles against systemic disease by regulating cytokine responses [25].…”