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

HLA-B-5701、-DRB*07 和 -DQ3 单倍型对阿巴卡韦超敏反应的易感性特征

• 批准号: nhmrc : 237408
• 负责人: A/Pr Campbell Witt
• 金额: $ 36.36万
• 依托单位: Murdoch University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/characterisation-susceptibility-abacavir-dq3-haplotype/94916
• 关键词: Characterisation; susceptibility; abacavir; hypersensitivity; carried

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.

药物超敏反应（HSR）是一种重要的医源性致病原因，甚至死亡。不幸的是，人们对潜在的机制知之甚少，因此很难预测哪些人可能有这些反应的风险。研究表明，HSR中特定药物与宿主免疫系统之间的相互作用与移植中观察到的相似，并且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意义，因为它决定了移植器官是“排斥”还是“接受”。我们已经确定了MHC遗传标记（HLA-B*5701，-DRB 1 *0701和-DQ 3）与HIV药物阿巴卡韦的HSR之间的显著关联。在72%（13-18）的有这种反应的个体中发现了这些标志物的携带，而在耐受阿巴卡韦的个体中发现了0%（0-185）（比值比822），因此预测100%病例中的HSR，97%的阿巴卡韦耐受性。这代表了一个最强大的MHC基因协会与临床综合征尚未描述。由于阿巴卡韦HSR影响约5%的阿巴卡韦使用者，因此预计了解这些遗传因素可显著降低易感个体发生HSR的风险，而不会不适当地拒绝使用阿巴卡韦。MHC和阿巴卡韦HSR在临床环境中的这种关联提供了一个独特的机会来阐明这种HSR的基础机制，这可能会让人们对药物HSR有更深入的了解。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。鉴于这种易于进行的基因检测在识别风险个体方面的高预测价值，临床上也有必要快速识别所涉及的基因，以提供尽可能有针对性的风险评估。