NOS2基因多态性与抗结核药物所致肝损伤易感性的相关性研究  

Association between NOS 2 gene polymorphisms and susceptibility of anti-tuberculous drug induced liver injury

作　　者：孙勤[1] 王鹏[1] 沙巍[1] 肖和平[1] Sun Qin;Wang Peng;Sha Wei;Xiao Heping.(Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, Chin)

机构地区：[1]同济大学附属上海市肺科医院结核病临床研究中心上海市结核(肺)重点实验室,200433

出　　处：《中华传染病杂志》2018年第1期12-17,共6页Chinese Journal of Infectious Diseases

基　　金：国家自然科学基金青年项目（81400006）;上海市浦江人才计划（16PJD041）

摘　　要：目的探讨抗氧化通路酶系NOS2基因多态性与抗结核药物所致肝损伤（anti-tuberculous drug induced liver injury，ATDILI）易感性的相关性。方法采用生物信息统计学方法筛选出NOS2基因16个tagSNP（Hardy-Weinberg平衡P〉0.001，最小等位基因频率〉0.1，r2〉0.8），采用SNPscan？多重SNP分型技术对461例ATDILI患者和466例非ATDILI患者的DNA样本进行基因分型，分析这些位点基因型和单倍型在病例组和对照组之间的频率差异，分析在显性、隐性和加性遗传模型下各个SNP位点与ATDILI易感性的关联性。结果所有位点的等位基因频率分布均符合Hardy-Weinberg平衡。NOS2基因rs9906835 G/A基因型、rs944725 T/C基因型、rs3794763 G/A基因型、rs3794764 G/A和A/A基因型以及rs6505469 T/A基因型均可增加ATDILI易感性（均P〈0.05），在显性遗传模型下，rs9906835、rs944725、rs3794763、rs3794764以及rs6505469可增加患者抗结核治疗后发生肝损伤的风险（均P〈0.05）；在加性遗传模型下，rs944725、rs3794763和rs3794764增加ATDILI发生的风险（均P〈0.05）。单倍型分析显示NOS2基因CGCATT、AC和AAA单倍型均可增加ATDILI发生的风险（均P〈0.05）。结论NOS2基因为ATDILI的易感基因。ObjectiveInducible isoform of NO synthase （iNOS）, coded by NOS2, is one of the antioxidant enzymes. The aim of this study is to explore the association between NOS2 gene polymorphisms and susceptibility of anti-tuberculous drug induced liver injury （ATDILI）.MethodsSixteen tagSNP of NOS2 gene were selected using systematic bioinformatic analysis （HWE-P〉0.001, MAF〉0.1, r2〉0.8）. A population based case-control study was performed to genotype 16 tagSNP of NOS2 gene in 461 ATDILI patients and 466 non-ATDILI patients using SNPscan？ technology. The genotype and haplotype frequencies were compared between case and control groups. Three genetic models including dominant, recessive and additive models were used to analyze the association between all the selected SNP polymorphisms and susceptibility of ATDILI.ResultsAll the alleles frequencies of these SNP were in Hardy-Weinberg equilibrium. NOS2 rs9906835 G/A genotype, rs944725 T/C genotype, rs3794763 G/A genotype, rs3794764 G/A and A/A genotype, rs6505469 T/A genotype were associated with increased risk for developing ATDILI （all P〈0.05）. NOS2 rs9906835, rs944725, rs3794763, rs3794764 and rs6505469 were associated with susceptibility of ATDILI in dominant model （all P〈0.05）. NOS2 rs944725, rs3794763 and rs3794764 were associated with increased risk for developing ATDILI in recessive model （all P〈0.05）. In addition, CGCATT, AC and AAA haplotypes of NOS2 gene were found to have association with susceptibility of ATDILI （all P〈0.05）.ConclusionOur study showed that NOS2 gene is a susceptible gene of ATDILI.

关 键 词：抗结核药 疾病遗传易感性 多态性 单核苷酸 肝损伤 NOS2基因 

分 类 号：R52[医药卫生—内科学] R575[医药卫生—临床医学]