NAT2基因多态性与抗结核药物性肝损害的关系  

Relationship between genetic polymorphisms of NAT2 and susceptibility to antituberculosis drug-induced liver injury

作　　者：朱冬林[1,2] 吴雪琼[1] 席云[2] 钟逾 张俊仙[1] 安慧茹[1] 

机构地区：[1]解放军第309医院全军结核病研究所,北京100091 [2]中山大学附属第三医院检验科,广东广州510630 [3]毅新兴业(北京)科技有限公司,北京100080

出　　处：《中国病原生物学杂志》2012年第6期406-413,共8页Journal of Pathogen Biology

基　　金："重大新药创制"科技重大专项资助项目(No.2010ZX09102-301);北京市科技计划研发攻关类科研基金资助项目(No.D08050700640802)

摘　　要：目的探讨汉族人群N-乙酰基转移酶2(NAT2)基因多态性与抗结核药物性肝损害(ATDLI)易感性的关系。方法回顾性分析抗结核治疗后发生肝损害的结核病患者228例(肝损害组),未发生肝损害的结核病患者260例(无肝损害组),应用时间飞行质谱技术(MassARRAY)检测NAT2基因多态性。结果在筛选出的10个标签单核苷酸多态性(tagSNP)位点中,NAT2启动子区域rs4646243的T等位基因和rs4646246的A等位基因构成的突变纯合及杂合基因型均与抗结核药物性肝损害保护性有关联,rs1115784、rs1041983和rs1799930的纯合突变基因型与抗结核药物性肝损害风险相关联,其中rs1041983和rs1799930的突变纯合基因型与抗结核药物性肝损害高度关联。在10个标签SNP位点中发现2个单体域,位于单体域1的单体型‘TGAA’和位于单体域2的单体型‘TAG’与抗结核药物性肝损害相关联。在NAT2基因上还发现2个抗结核药物性肝损害保护性的单体型:位于单体域1的单体型‘CGGG’及位于单体域2的‘CGG’。结论汉族人群NAT2基因多态性与抗结核药物性肝损害的发生密切相关,通过检测NAT2基因及单体型,可以在抗结核治疗前筛选出肝损害发生风险较高的患者。Objective To investigate the relationship between the genetic polymorphisms of N-acetyltransferase 2 （NAT2） and the susceptibility of antituberculosis drug-induced hepatotoxicity （ATDLI） in patients with tuberculosis in the Chinese Han population. Methods Genetic polymorphisms of NAT2 were analyzed with MassARRAY in patients with tuberculosis （228 with hepatotoxicity and 260 without hepatotoxicity） after treatment with an antituberculosis drug. Results Genotypes with the T allele of rs4646243 and A allele of rs4646246 in the promoter area of NAT2 were found to significantly protect against ATDLI. In addition, the homozygous genotype with the minor alleles rs1115784, rs1041983, and rs1799930 was significantly associated with the development of ATDLI. The homozygous mutated geno- type with rs1041983 and rs1799930 was associated with a higher risk of ATDLI. Two blocks in 10 tagging $NPs were identified, and the haplotype ＂TGAA＂ in block 1 and ＇TAG＇ in block 2 were significantly associated with ATDLI. Addition ally, two haplotypes were associated with protection from ATDLI： ＇CGGG＂ in block 1 and ＂CGG＇ in block 2. Conclusion NAT2 genotypes may be significant associated with the risk of ATDLI in the Chinese Han population and could be used to forecast patients at-risk of ATDLI before initiating treatment for TB.

关 键 词：N-乙酰基转移酶2 时间飞行质谱技术 结核 肝损害 基因多态性 

分 类 号：R978.3[医药卫生—药品]