遗传异质性药物毒副作用与HLA基因关联及分子机制研究进展

The associations between idiosyncratic adverse drug reactions and HLA alleles and their underlying mechanism

摘要:
随着高通量基因测序技术的发展, 全基因组关联分析 (genome-wide association study, GWAS) 被越来越多地应用到遗传异质性药物毒副作用 (adverse drug reactions, ADRs) 研究中。越来越多的研究发现: 遗传异质性ADRs与人类白细胞抗原 (human leukocyte antigen, HLA) 密切相关, 如阿巴卡韦 (abacavir) 与HLA-B*5701、别嘌醇 (allopurinol) 与HLA-B*5801、卡马西平 (carbamazepine) 与HLA-B*1502等基因关联。针对上述基因关联现象, 相继提出半抗原理论、危险因子理论、“P-I”理论以及最新提出的自身免疫机制。本文就遗传异质性ADRs与HLA基因关联及其机制研究的最新进展进行了详细综述。

Abstract:
With the advent of Twenty-First century, more and more genome-wide association studies (GWAS) showed that idiosyncratic adverse drug reactions (ADRs) were closely related with human leukocyte antigen (HLA) alleles, such as the associations of abacavir-HLA-B*5701, allopurinol-HLA-B*5801, and carbamazepine- HLA-B*1502, etc. To explore the mechanisms of these idiosyncratic drug reactions, hapten hypothesis, danger signal hypothesis, pharmacological interaction (P-I) concept and autoimmune mechanism are proposed. In this paper, recent GWAS studies on the HLA-mediated adverse drug reactions and underlying mechanism are reviewed in detail.