TLR2和TLR4基因多态性及启动子区CpG岛甲基化与抗结核药物性肝损伤的关系  

Study on the relationship between TLR2 and TLR4 polymorphism and CpG island methylation and anti-tuberculosis drug-induced liver injury

作　　者：李玥 马烁 刘越 唐琴艳 郭玉 刘洋 裴盛斐 冯福民 LI Yue;MA Shuo;LIU Yue;TANG Qinyan;GUO Yu;LIU Yang;PEI Shengfei;FENG Fumin(School of Public Health,North China University of Science and Technology,Hebei Provincial Collaborative Innovation Center for Occupational Health and Safety,Tangshan 063210,China;Department of Preventive Health Care,Kailuan General Hospital,Tangshan 063000,China)

机构地区：[1]华北理工大学公共卫生学院预防医学系,河北省职业卫生与安全协同创新中心,唐山063210 [2]开滦总医院预防保健科,唐山063000

出　　处：《中华疾病控制杂志》2025年第2期217-223,共7页Chinese Journal of Disease Control & Prevention

基　　金：国家自然科学基金(81041096)。

摘　　要：目的研究Toll样受体(Toll-like receptors,TLRs)家族成员中Toll样受体2(Toll-like receptor 2,TLR2)和Toll样受体4(Toll-like receptor 4,TLR4)基因的单核苷酸多态性(single nucleotide polymorphism,SNP)位点rs7656411、rs3804099、rs1927914、rs1927911及TLR2基因启动子区CpG岛(CpG island)甲基化与抗结核药物性肝损伤(anti-tuberculosis drug-related liver injury,ADLI)的关系。方法2019年7月―2022年3月在招募的结核病患者中选择322名发生ADLI的患者和322名未发生ADLI的患者分别作为病例组和对照组,按照性别、年龄和治疗方案进行1∶1匹配。通过甲基化特异性聚合酶链式反应(polymerase chain reaction,PCR)法和聚合酶链式反应-限制性片段长度多态性(PCR-restriction fragment length polymorphism,PCR-RFLP)技术检测基因多态性以及甲基化特征。结果ADLI患者中TLR2基因rs3804099位点野生基因型(OR=0.55,95%CI:0.31~0.96)、CpG岛甲基化发生率高于对照组(OR=1.81,95%CI:1.07~3.06)。多变量分析表明TLR2基因rs3804099位点野生型TT与ADLI疾病进展相关,野生型TT可能为ADLI的保护因素OR=0.53(95%CI:0.38~0.75)。此外,TLR2基因CpG岛高甲基化与ADLI的发生风险独立相关[调整OR=1.86(95%CI:1.05~3.28)]。rs3804099位点突变型和CpG岛高甲基化的交互作用增加了ADLI的发生风险,为对照组的2.12倍(OR=2.12,95%CI:1.36~3.29)。结论TLR2基因多态性和CpG岛甲基化与ADLI有关。TLR2基因启动子区CpG岛甲基化与其rs3804099位点基因多态性之间存在交互作用与ADLI的高风险有关。Objective To investigate the relationship between single nucleotide polymorphisms rs7656411,rs3804099,rs1927914,rs1927911 in Toll-like receptor 2(TLR2)and Toll-like receptor 4(TLR4)genes,as well as CpG island methylation in the TLR2 gene promoter region,and anti-tuberculosis drug-induced liver injury(ADLI).Methods From July 2019 to March 2022,322 tuberculosis patients with ADLI and 322 tuberculosis patients without ADLI were selected and matched 1∶1 based on gender,age,and treatment regimen.Gene polymorphisms and methylation patterns were detected using methylation-specific polymerase chain reaction(PCR)and PCR-restriction fragment length polymorphism(PCR-RFLP)technique.Results The wild-type genotype of TLR2 gene rs3804099 site(OR=0.55,95%CI:0.31-0.96)and CpG island methylation rate(OR=1.81,95%CI:1.07-3.06)were significantly higher in ADLI patients than in the control group(P<0.05),with no statistical difference in the genotype frequency of other polymorphic sites between the two groups.Multivariate analysis showed that the wild-type TT of TLR2 gene rs3804099 site was associated with the progression of ADLI,and the wild-type TT may be a protective factor for ADLI OR=0.53(95%CI:0.38-0.75).In addition,high methylation of CpG island in TLR2 gene was independently associated with the risk of ADLI,with adjusted OR of 1.86(95%CI:1.05-3.28).The interaction between the mutation of rs3804099 site and high methylation of CpG island increased the risk of ADLI,being 2.12 times that of the control group(OR=2.12,95%CI:1.36-3.29).Conclusions There is an association between TLR2 gene polymorphism and CpG island methylation and ADLI.The interaction between CpG island methylation in the TLR2 gene promoter region and the gene polymorphism at rs3804099 is associated with a high risk of ADLI.

关 键 词：基因多态性 抗结核药 肝损伤 甲基化 

分 类 号：R183.3[医药卫生—流行病学] Q756[医药卫生—公共卫生与预防医学]