Center for Human Genome Variation, Duke University, Durham, NC, USA.
Pharmacogenet Genomics. 2012 Nov;22(11):784-95. doi: 10.1097/FPC.0b013e3283589a76.
Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs.
DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases.
After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5×10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables.
Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study.
药物性肝损伤（DILI）是一种严重的药物不良反应，据推测其具有遗传成分。我们对 783 名经历了由 200 多种相关药物引起的 DILI 的欧洲血统个体进行了全基因组关联研究。
来自美国药物性肝损伤网络（Drug-Induced Liver Injury Network，DILI-Net）的 DILI 患者（n=401）和三个国际登记处（n=382）使用 Illumina 1Mduo BeadChip 进行基因分型，并与 3001 名人群对照进行比较。在 307 个独立的 DILI-Net 病例中测试了潜在的关联。
在考虑了 flucloxacillin-DILI 和 amoxicillin/clavulanate-DILI 的已知主要组织相容性复合体风险等位基因后，没有全基因组显著关联，包括主要组织相容性复合体区域。根据临床表型（损伤类型、潜伏期、发病年龄）对 DILI 病例进行分层也没有显示出显著关联。对先前与自身免疫性疾病相关的 193 个单核苷酸多态性进行了肝细胞性 DILI（n=285）的分析，结果显示信号转导和转录激活因子 4（STAT4）附近的 rs7574865 存在趋势关联（P=4.5×10(-4)）。在 168 例肝细胞性 DILI 病例的独立队列中，这一关联得到了复制（合并队列的 P=0.011 和 1.5×10(-5)）。没有发现与其他临床或人口统计学变量分层相关的显著关联。
尽管在全基因组水平上没有达到显著水平，但肝细胞性 DILI 与 STAT4 之间的关联与免疫系统在 DILI 中的作用相一致。然而，全基因组关联研究结果的缺乏支持这样一种观点，即 DILI 的强烈遗传决定因素可能在很大程度上是药物特异性的，或者可能反映了我们研究中未评估的罕见遗传变异。
