National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.
Liver Int. 2015 Jul;35(7):1801-8. doi: 10.1111/liv.12836. Epub 2015 Apr 20.
In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI.
与研究遗传变异与其他复杂特征的相关性的研究相比，那些研究肝毒性的研究已经确定了与药物性肝损伤（DILI）易感性相关的风险等位基因，其风险比要高得多。此外，相对较少的人类白细胞抗原（HLA）等位基因与多种不良反应（包括 DILI、皮肤过敏和药物性胰腺炎）重叠相关。然而，如果在处方前用作测试以预防潜在的不良反应，基因分型将具有非常高的阴性预测值，但由于 DILI 的发生率较低，阳性预测值较低。一个潜在的考虑因素是将所有相关的 HLA 基因型视为一个涵盖不同形式药物不良反应的面板，从而提高面板的阳性预测值并扩大其应用范围。与 DILI 相关的大多数 HLA 等位基因具有非常高的阴性预测值；因此，它们可用于排除特定药物引起的肝毒性。当患者同时接触两种可能导致 DILI 的药物时，遗传测试的高阴性预测值可用于确定 DILI 的正确药物。在怀疑发生 DILI 的情况下，将遗传测试纳入事件的因果关系评估中，可能会提高因果关系评估工具的一致性和准确性。最近的一项临床试验使用 N-乙酰转移酶 2 基因分型来确定抗结核治疗方案中异烟肼的适当剂量，证明基于药物遗传学的临床算法有可能提高药物的疗效并降低 DILI。
