收稿日期: 2024-11-08
网络出版日期: 2025-02-28
基金资助
江苏省中医药科技发展计划项目(YB2020037);南京市卫生科技发展专项资金项目(YKK22127);南京感染病学临床医学中心、江苏省传染病医学创新中心(CXZX202232)
Study on the relationship between UGT1A1 polymorphism and UGT1A1 inhibitory drugs⁃induced liver injury
Received date: 2024-11-08
Online published: 2025-02-28
目的 基于药物基因组学探讨UGT1A1抑制药物相关药物性肝损伤（DILI）与其基因多态性的关系。 方法 收集2022年6月至2024年6月诊断为DILI的住院患者可能导致肝损伤的相关药物信息、血常规、肝功能等结果，查找相关数据库把DILI患者相关药物分为UGT1A1抑制药物和非UGT1A1药物；并采用Sanger测序或MassARRAY SNP 分型技术对UGT1A1基因进行检测与分型。 结果 共纳入219例DILI患者，男性98例，平均年龄（46.32 ± 14.95）岁，查找相关数据库DILI患者有20个药物（16.26%，20/123）对UGT1A1酶有抑制作用。UGT1A1抑制药物相关DILI占60.73%（133/219）。UGT1A1抑制药物组的ALT、AST、ALP、GGT高于非UGT1A1药物组（P < 0.05）；而年龄、性别、TBIL、IBIL、WBC、Hb、Plt、损伤类型、损伤分级差异均无统计学意义（P > 0.05）。UGT1A1抑制药物组的UGT1A1多态性位点占比（68.42%）高于非UGT1A1药物组［51.16%，OR（95% CI）： 2.068 （1.183 ~ 3.617），χ2 = 6.58，P = 0.01］。UGT1A1抑制药物组与非UGT1A1药物组基因分类占比差异有统计学意义（χ 2 = 9.60，P = 0.022）。在logistic单因素分析中ALT和UGT1A1*6与UGT1A1抑制药物相关DILI相关，多因素分析中UGT1A1*6［OR（95% CI）： 3.143（1.398 ~ 7.067），P = 0.006］与UGT1A1抑制药物相关DILI显著相关。 结论 UGT1A1*6增加UGT1A1抑制药物相关DILI的发生。
陆雨佳 , 区可滢 , 马越洋 , 袁传溯 , 刘斌 , 杨永峰 , 熊清芳 . UGT1A1多态性与UGT1A1抑制药物相关药物性肝损伤的关系[J]. 实用医学杂志, 2025 , 41(4) : 588 -593 . DOI: 10.3969/j.issn.1006-5725.2025.04.019
Objective To investigate the association between UGT1A1 inhibitors-induced liver injury （DILI） and UGT1A1 gene polymorphisms through a pharmacogenomics approach. Methods Information on relevant drugs that may induce liver injury， blood routine tests， and liver function tests was collected from hospitalized patients diagnosed with DILI between June 2022 and June 2024. Relevant databases were searched to categorize DILI-associated drugs into UGT1A1 enzyme inhibitors and those without interaction with UGT1A1. Sanger sequencing or MassARRAY SNP typing technology was utilized to detect and genotype the UGT1A1 gene. Results A total of 219 patients with drug-induced liver injury （DILI） were enrolled， including 98 males， with a mean age of 46.32 ± 14.95 years. A literature search of relevant databases revealed that 20 drugs （16.26%， 20/123） associated with DILI had inhibitory effects on the UGT1A1 enzyme. The proportion of DILI cases related to UGT1A1 inhibitors was 60.73% （133/219）. Compared to non-UGT1A1 inhibitor-related DILI group， the UGT1A1 inhibitor-related DILI group exhibited significantly higher levels of ALT， AST， ALP， and GGT （P < 0.05）， while no significant differences were observed in age， gender， TBIL， IBIL， WBC， Hb， PLT， injury type， or injury grade （P > 0.05）. The prevalence of UGT1A1 polymorphisms was significantly higher in the UGT1A1 inhibitor-related DILI group （68.42%） compared to the non-UGT1A1 inhibitor-related DILI group （51.16%）， with an odds ratio （OR） of 2.068 （95% CI： 1.183 to 3.617； χ2 = 6.58， P = 0.010）. There was also a significant difference in the distribution of genotypes between the UGT1A1 inhibitor-related and non-UGT1A1 inhibitor-related DILI groups （χ2 = 9.60， P = 0.022）. Univariate logistic regression analysis indicated that ALT and UGT1A1*6 were associated with UGT1A1 inhibitor-related DILI， while multivariate analysis confirmed that UGT1A1*6 was independently associated with UGT1A1 inhibitor-related DILI ［OR（95%CI） = 3.143 （1.398 to 7.067）， P = 0.006］. Conclusion The UGT1A1*6 allele increases the susceptibility to drug-induced liver injury （DILI） associated with UGT1A1 inhibitory drugs.
Key words： drug-induced liver injury; gene polymorphism; UGT1A1; drug; inhibitor
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