Parham L R, Briley L P, Li L, Shen J, Newcombe P J, King K S, Slater A J, Dilthey A, Iqbal Z, McVean G, Cox C J, Nelson M R, Spraggs C F
GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
GlaxoSmithKline Research & Development, Stevenage, UK.
Pharmacogenomics J. 2016 Apr;16(2):180-5. doi: 10.1038/tpj.2015.40. Epub 2015 May 19.
Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB107:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB107:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.
拉帕替尼与严重肝损伤的低发生率相关。先前的研究已确定并证实II类等位基因HLA - DRB107:01与拉帕替尼诱导的肝损伤密切相关；然而，其适度的阳性预测值限制了其临床应用。为了评估位于主要组织相容性复合体基因座内或基因组其他位置的其他遗传变异是否可能影响拉帕替尼诱导的肝损伤风险，并有可能导致具有更高预测质量的遗传关联，我们采用了两种方法：全基因组关联研究和全基因组测序研究。除了先前确定的HLA - DRB107:01关联外，该评估未发现其他关联。本研究是对药物性肝损伤（DILI）或超敏反应最全面的遗传评估，并表明研究人类白细胞抗原与DILI和其他超敏反应之间可能的关联是理解这些事件机制的重要第一步。
