Urban Thomas Jacob, Nicoletti Paola, Chalasani Naga, Serrano José, Stolz Andrew, Daly Ann K, Aithal Guruprasad P, Dillon John, Navarro Victor, Odin Joseph, Barnhart Huiman, Ostrov David, Long Nanye, Cirulli Elizabeth Trilby, Watkins Paul Brent, Fontana Robert John
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
J Hepatol. 2017 Jul;67(1):137-144. doi: 10.1016/j.jhep.2017.03.010. Epub 2017 Mar 18.
BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.
Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.
Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI.
HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.
Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.
米诺环素肝毒性在既往健康个体中可表现出显著的自身免疫特征。本研究的目的是在一组表型明确的患者队列中确定米诺环素药物性肝损伤（DILI）的遗传决定因素。
对患有米诺环素DILI的白种人患者进行全基因组基因分型，并与未接触药物的人群对照进行比较。使用AutoDock Vina评估米诺环素与人白细胞抗原（HLA）的结合情况。
25例患者中，80%为女性，中位年龄为19岁，从开始用药到发生DILI的中位潜伏期为318天。就诊时，76%的患者有急性肝细胞性肝损伤，中位丙氨酸氨基转移酶（ALT）为1077U/L（范围：63至2333），中位胆红素为4.5mg/dl（范围：0.2至16.7），90%的患者抗核抗体（ANA）呈阳性。在随访期间，50%的患者接受了皮质类固醇治疗，没有参与者死亡或需要进行肝移植。发现HLA-B∗35:02与米诺环素DILI风险之间存在显著关联；DILI病例中的携带频率为16%，而人群对照中的携带频率为0.6%（比值比：29.6，95%置信区间：7.8 - 89.8，p = 2.5×10）。基于序列的HLA分型证实了HLA-B∗35:02基因分型的验证。与非携带者相比，HLA-B∗35:02携带者具有相似的就诊特征和结局。计算机模拟研究支持这样的假设，即米诺环素与这种新的HLA风险等位基因的直接结合可能是米诺环素DILI的一个重要起始事件。
HLA-B∗35:02是一种罕见的HLA等位基因，在25例米诺环素DILI病例中比在人群对照中更频繁地被鉴定出来。如果在其他队列中得到证实，这种HLA等位基因可能被证明是米诺环素DILI的一个有用的诊断标志物。
长期使用米诺环素治疗痤疮后发生肝损伤是一种罕见但可能严重的药物性肝损伤形式。我们的研究表明，HLA-B∗35:02携带者发生米诺环素相关肝损伤的风险增加。这些结果可能有助于医生更快速、自信地诊断受影响的患者，并可能降低未来接受米诺环素治疗的个体发生肝损伤的风险。
