Characterisation of susceptibility to abacavir hypersensitivity carried on the HLA-B-5701, -DRB*07 and -DQ3 haplotype

药物超敏反应(HSR)是医源性致病，甚至致死的重要原因。不幸的是，人们对这些反应的潜在机制知之甚少，因此很难预测哪些人可能面临这些反应的风险。研究表明，在HSR中，特定药物与宿主免疫系统之间的相互作用类似于在移植中观察到的，人类基因组的主要组织相容性复合体(MHC)区域在这种情况下具有重要作用，就像它在确定移植器官是被拒绝还是被接受时一样。我们已经发现MHC遗传标记(人类白细胞抗原-B*5701、-DRB1*0701和-DQ3)与HIV药物阿巴卡韦的HSR显著相关。这些标记物的携带率为72%(13-18)，在阿巴卡韦耐受者中为0(0-185)(优势比为822)，从而预测HSR的发生率为100%，阿巴卡韦耐受率为97%。这代表了迄今已描述的与临床综合征最强大的MHC基因关联之一。由于abacavir HSR影响到约5%的abacavir使用者，了解这些遗传因素预计将显著降低易感人群患HSR的风险，而不会不适当地拒绝使用abacavir。在临床环境中，MHC和abacavir HSR之间的这种联系提供了一个独特的机会来描述这种HSR背后的机制，这可能会给一般的药物HSR提供洞察力。在公共领域而不是在商业部门继续支持这项研究，将确保商业考虑不会限制这些研究结果的传播。鉴于这种易于操作的基因测试在识别高危个体方面具有很高的预测价值，临床上也有必要快速识别所涉及的基因(S)，以提供尽可能有针对性的风险评估。

Drug hypersensitivity reactions (HSR) are a significant iatrogenic cause of morbidity, and even of mortality. Unfortunately the underlying mechanisms are poorly understood, making it difficult to predict which individuals may be at risk of these reactions. Research indicates that the interaction between specific drugs and the host immune system in HSR is similar to that observed in transplantation and that the major histocompatibility complex (MHC) region of the human genome assumes importance in this setting, as it does in determining if a transplanted organ is 'rejected' or 'accepted'. We have identified a striking association between MHC genetic markers (HLA-B*5701, -DRB1*0701, and -DQ3) and HSR to the HIV drug abacavir. Carriage of these markers was found in 72% (13-18) of individuals with this reaction, and 0% (0-185) of those who tolerated abacavir (odds ratio 822), thus predicting HSR in 100% of cases, and abacavir tolerance in 97%. This represents one of the most powerful MHC gene associations with a clinical syndrome yet described. As abacavir HSR affects ~5% of abacavir users, knowledge of these genetic factors would be predicted to significantly reduce the risk of susceptible individuals developing HSR, without inappropriately denying access to abacavir. This association between the MHC and abacavir HSR in the clinical setting provides a unique opportunity to characterise mechanisms that underlie this HSR, which may give insights into drug HSR generally. Continued support of this research in the public domain, rather than in the commercial sector, will ensure that commercial considerations do not restrict the dissemination of these findings. Given the high predictive value of this readily performed genetic test in identifying at-risk individuals, there is also a clinical imperative to rapidly identify the gene(s) involved, to provide the most targeted risk assessment possible.