羧酸酯酶基因1多态性鉴定及其与抗结核药物肝毒性相关性研究  

The relationship between carboxylesterase 1 gene polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity

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

机构地区：[1]解放军第三0九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 [3]毅新兴业(北京)科技有限公司

出　　处：《中华内科杂志》2012年第7期524-530,共7页Chinese Journal of Internal Medicine

基　　金：“重大新药创制”科技重大专项（2010ZX09102-301）;北京市科技计划研发攻关类科研基金（D08050700640802）

摘　　要：目的研究羧酸酯酶（CES）基因1多态性及其与抗结核药物肝毒性易感性之间的关系。方法应用PCR一时间飞行质谱技术（PCR．MassArray）分析473例抗结核治疗后发生肝损害（200例）和未发生肝损害（273例）结核病患者的CES1基因多态性，并通过统计学分析CESl各单核苷酸多态性（SNP）位点基因型与抗结核药物所致肝毒性之间的关系。结果在筛选出的4个CESl标签SNP位点中，rs1968753的等位基因频率在肝损害和无肝损害组间存在分布差异（P=0．0236）。SNP1rs8192950（P=0．044，OR=0．649，95％CI=0．426—0．989，AC／AA）和SNP2rs1968753（P=0．048，OR：0．556，95％CI=0．311～0．995，GG／AA）与抗肝毒特性有显著关联。由‘CGC’参与构成的双单体型，在1份拷贝时表现出显著的肝毒保护性（P=0．048，OR=0．654，95％CI=0．430—0．996）。结论CES1基因多态性可能与抗结核药物性肝损害密切相关，SNPrs8192950的AC基因型和rs1968753的GG基因型可能成为抗结核药物肝毒性风险预测的候选突变。Objective To study the relationship between the genetic polymorphisms of carboxylesterase 1 gene （CES1） and the susceptibility to antituberculosis drug-induced hepatotoxicity （ATBDIH）. Methods Genetic polymorphisms of CES1 in 473 tuberculosis patients with or without hepatotoxicity （200：273） after antituberculosis chemotherapy were analyzed by PCR-MassArray. Results In 4 tags of CES1 single nueleotide polymorphism （ SNP ）, the frequency of the rs1968753 allele had statistical difference between the hepatotoxicity group and the no-hepatotoxieity group （ P = 0. 0236 ）. The characteristics of anti-hepatotoxicity had been shown relationship with rs8192950 （ P = 0. 044, OR = 0. 649, 95%CI = 0. 426-0. 989, AC/AA） and rs1968753 （P =0.048,OR =0.556,95% CI =0.311-0.995, GG/AA）. The diplotypes with ＇ CGC＇ haplotype exhibited significant protection against hepatotoxieity at one copy （ P = 0. 048, OR = 0. 654, 95% CI = 0. 430-0. 996 ）. Conclusions The genetic polymorphisms of CES1 might have significant association with ATBDIH. SNP rs8192950 AC genotype and rs1968753 GG genotype might be the candidates for risk prediction of ATBDIH.

关 键 词：结核 肝损害 羧酸酯酶基因1 基因多态性 

分 类 号：R52[医药卫生—内科学]