N-乙酰化转移酶2基因多态性与抗结核药物所致肝损伤的相关性

目的 探讨N-乙酰化转移酶2(NAT2)基因多态性与抗结核药致肝损伤(ADIH)的相关性.方法 以抗结核治疗3个月内出现肝损伤的106例结核患者为病例组,未出现肝损伤的106例结核患者为配对对照.采用1:1匹配的病例对照研究和聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术,检测106对结核患者的NAT2基因481C/T、590G/A、857G/A位点多态性情况,并对主要环境影响因素和基因型进行单因素和多因素条件Logistic回归分析.结果 病例组NAT2基因的481C/T、590G/A、857G/A位点的T、A、A等位基因频率分别为7.5%、28.8%、17.9%,对照组分别为6.6%、18.9%、17.5%.病例组NAT2慢速乙酰化型的频率明显高于对照组,粗OR值为2.250(95%CI为1.140～4.441).对文化程度、职业、体质指数(BMI)、吸烟、饮酒和结核类型6个可疑危险因素进行了单因素分析,仅低BMI和饮酒为ADIH发生的危险因素.在多因素分析中调整BMI、饮酒两个因素后,NAT2乙酰化程度仍与ADIH的发生显著相关,调整OR值为2.246(95%CI为1.086～4.644).结论 NAT2基因慢速乙酰化型町能与ADIH的发生有关.     

GSTA1、GSTM3基因多态性与汉族结核患者抗结核药物性肝损伤的关系

目的分析GSTA1、GSTM3基因多态性与汉族结核患者抗结核药物性肝损伤(ADIH)的关系。方法选取上海市解放军第85医院2014年5月—2016年5月收治的汉族初治及复治结核患者66例,根据肝损伤情况分为对照组(未发生肝损伤)和观察组(发生肝损伤),每组33例。比较两组患者GSTA1、GSTM3基因型及等位基因分布频率,分析GSTA1、GSTM3交互作用与ADIH的关系,而GSTA1、GSTM3基因多态性与ADIH的关系分析采用多因素Logistic回归分析。结果观察组患者GSTA1 CC基因型及C等位基因分布频率低于对照组(P0.05),GSTA1 CT基因型及T等位基因分布频率高于对照组(P0.05);两组患者GSTA1 TT基因型及GSTM3 AA、AB、BB基因型及A、B等位基因分布频率比较,差异无统计学意义(P0.05)。以GSTA1(C)/GSTM3(A)为对照,GSTA1(T)/GSTM3(B)交互作用与汉族结核患者ADIH相关(P0.05)。多因素Logistic回归分析结果显示,GSTA1基因多态性是汉族结核患者ADIH的危险因素[OR=1.772,(1.126,2.787),P0.05]。结论 GSTA1基因多态性与汉族结核患者ADIH相关,而GSTM3基因多态性与汉族结核患者ADIH无关。     

中国汉族人群谷胱甘肽硫转移酶M1及T1基因多态性与先天性心脏病发病风险的关系

目的探讨中国汉族人群谷胱甘肽硫转移酶(glutathione S-transferases,GST)M1及T1基因(GSTM1/GSTT1)多态性与先天性心脏病(先心病)发病风险的关系。方法采用病例-对照研究(病例组365例,对照组372例),运用多重聚合酶链反应检测先心病患者及健康对照GSTM1/GSTT1基因型;并利用多因素非条件logistic回归模型,进行先心病发病风险影响因素关联强度及交互作用分析。结果 GSTM1/GSTT1基因多态性及研究对象母亲围孕期吸烟、饮酒、化学物质接触、孕前体质量指数、教育程度、定期产检以及怀孕知情时间在病例组和对照组之间分布存在明显差异(P<0.05)。GSTM1/GSTT1基因缺失与先心病发病风险显著正相关(OR=1.56,P=0.049;OR=1.73,P=0.036)。经logistic回归分析,GSTM1(-)/GSTT1(-)基因型和研究对象母亲围孕期吸烟、饮酒、化学物质接触以及孕前高体质量指数是先心病发病的高危因素,研究对象母亲围孕期定期产检以及摄入充足的叶酸是先心病的保护因素。研究对象母亲围孕期吸烟与GSTM1(-)/GSTT1(-)基因型之间具有正相加交互作用,与母亲围孕期不吸烟且GSTM1/T1基因未缺失的研究对象相比,其母亲围孕期吸烟且携带GSTM1(-)和(或)GSTT1(-)基因型的先心病发病风险显著上升(OR=9.01,3.87,3.01;95%CI:1.73～39.69,1.21～19.57,1.13～9.69)。结论 GSTM1/GSTT1基因缺失是先心病发病风险的独立危险因素;GSTM1(-)/GSTT1(-)基因型与孕母围孕期吸烟在先心病的发生中具有协同作用。     

细胞色素P45O 2E1基因多态性与抗结核药物致肝损伤的关系

目的 探讨细胞色素P450(CYP)2E1基因多态性与抗结核药物所致肝损伤(ADIH)的关系.方法 采用病例对照研究设计,选择符合条件的339例结核患者为研究对象,调查其一般情况及肝功能,聚合酶链反应-限制性片段长度多态性分析进行基因分型.数据行单因素和多因素Logistic回归分析.结果 ADIH病例组103例结核患者CYP 2E1的7632T/A、101 9C/T、1259G/C等位基因频率分别为17.5%、26.2%和27.2%,对照组236例结核患者分别为29.7%、39.4%和40.7%(x2=5.539,P＜0.05;x2=5.458,P＜0.05;x2=5.628,P＜0.05).经多因素Logistic回归分析调整了性别、职业、饮酒等危险因素后,7632T/A、1019C/T、1259G/C位点多态性与ADIH的发生仍有相关性,且7632T/A与1019C/T及1259G/C位点野生基因型在ADIH发生过程中起协同作用.结论 携带CYP 2 E1的7632T/A、1019C/T和1259G/C位点野生基因型的个体发生ADIH的危险性增高,且在ADIH的发病过程中起协同作用.     

N-乙酰基转移酶2及谷胱甘肽S转移酶M1基因多态性与抗结核药物性肝损伤的关系研究

目的 研究药物代谢酶NAT2、GSTM1、GSTT1的基因多态性与抗结核药物肝损伤的关系,阐明抗结核药物性肝损伤（antituberculosis drug induced liver injury,ATDILI）的分子机制.方法 解放军第三○九医院结核科2008-2009年度住院初治结核病患者208例,具有明确抗结核药物性肝损伤发生的患者为肝损伤组（共101例）,无抗结核药物性肝损伤发生的患者为对照组（共107例）,通过PCR扩增产物直接测序的方法分析两组的NA T2基因多态性并分型.通过多重PCR方法检测两组患者GSTM1、GSTT1是否存在基因型缺失.以SPSS12.0软件进行x2检验处理,比较两组之间各基因型分布频率的差异,并计算各基因型风险系数（odds ratio,OR值）及95％可信区间（95％ CI）,分析疾病与基因的关联强度.结果 （1）肝损伤组患者中,39.6％ （40/101）为NAT2慢乙酰化基因型;对照组中,12.2％（13/107）为NA T2慢乙酰化基因型.NA T2慢乙酰化基因型者发生抗结核药物性肝损伤的风险系数（OR值）为4.74（95％CI＝2.42～9.28;x2 =20.62,P＜0.05）.（2）肝损伤组中,GSTM1缺失基因型占63.4％（64/101）,对照组GSTM1缺失基因型占51.4％（55/107）;两组比较GSTM1缺失基因型发生药物性肝损伤的OR值偏高（但无统计学意义）,为1.64（95％CI＝0.94～2.84,x2＝3.038,P＞0.05）.肝损伤组中,GSTT1缺失基因型占47.5％（48/101）,对照组GSTT1缺失基因型占45.8％（49/107）,两组比较OR值接近,为1.07（95％CI＝0.62～1.85,x2＝0.063,P＞0.05）.（3）肝损伤组中同时具有NA T2慢乙酰化基因型及GSTM1缺失基因型的患者29例,对照组5例,发生抗结核药物性肝损伤的风险系数OR值高达10.21（95％CI＝3.87～26.96,x2＝20.62,P＜0.005）.结论 NAT2基因的慢乙酰化基因型及GSTM1缺失基因型可能与ATDILT有关.     

2型糖尿病微量白蛋白尿与动脉硬化危险因素关系的研究

目的研究2型糖尿病(T2DM)微量白蛋白尿(MAU)与致动脉粥样硬化危险因素间的关系。方法回顾分析1995—2009年在卫生部北京医院住院的T2DM患者1004例,按尿白蛋白排泄率(UAER)分为MAU组及正常组,进行两组间患者临床和生化指标的比较,并进行MAU与致动脉硬化危险因素间的相关性分析。结果 (1)两组在性别、年龄、体重指数、收缩压、吸烟史、糖尿病病程、糖化血红蛋白、空腹血糖、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、血肌酐、尿酸、胰岛素抵抗指数等方面比较差异有统计学意义(P0.05);(2)Logistic回归分析显示,体重指数(OR=1.137,95%CI:1.061～1.218)、收缩压(OR=1.033,95%CI:1.023～1.043)、糖尿病病程(OR=1.082,95%CI:1.056～1.108)、糖化血红蛋白(OR=1.172,95%CI:1.019～1.349)、低密度脂蛋白胆固醇(OR=1.346,,95%CI:1.090～1.661)是MAU发生的独立危险因素。结论 T2DM患者MAU的发生与体重指数、收缩压、糖尿病病程、糖化血红蛋白、低密度脂蛋白胆固醇密切相关。     

谷胱甘肽转移酶T1位点基因多态性与中国人群肺癌易感性的Meta分析

目的用Meta分析的方法定量评价谷胱甘肽转移酶(GST)T1位点基因多态性与中国人群肺癌易感性的相关性。方法计算机检索EMBASE、Pub Med、Cochrane Library、中国生物医学文献数据库、中国期刊全文数据库、中文科技期刊数据库以及万方数据库,收集GSTT1位点基因多态性与中国人群肺癌易感性的病例对照试验。以病例组和对照组GSTT1基因位点基因型分布的比值比(OR)为疗效测量指标,采用STATA10.0软件进行统计分析。结果最终纳入19篇病例对照研究进行Meta分析,病例组共纳入肺癌患者2 356例,对照组共纳入健康志愿者3 260例。Meta分析结果显示:CSTT1基因功能型和缺失型在肺癌的发生率方面差异有统计学意义[OR=1.27,95%CI(1.06~1.52)]。结论 GSTT1基因缺失型可能增加了中国人群患肺癌的易感性。     

抗结核药物导致肝损伤的临床特征及危险因素分析

目的总结分析抗结核药物导致肝损伤的临床特征及危险因素。方法选取2017年1月—2018年12月在深圳市第三人民医院诊断为抗结核药物导致肝损伤的129例住院患者,分为肝功能异常组51例(39.53%),药物性肝损伤组78例(60.47%),其中肝衰竭13例(10.08%)。回顾性分析患者的实验室指标、治疗和预后资料。计数资料两组间比较采用χ~2检验,正态分布的计量资料两组间比较采用独立样本t检验,非正态分布的计量资料两组间比较采用Mann-Whitney U秩和检验。通过多因素logistic回归分析药物性肝损伤、肝衰竭的风险因素。结果药物性肝损伤组和肝功能指标异常组间合并慢性HBV感染比例(χ~2=5.616,P=0.018)、无症状肝损伤比例(χ~2=9.451,P=0.002)、肝衰竭比例(χ~2=9.453,P=0.002)、需调整抗结核方案比例(χ~2=16.787,P0.001)、首次肝损伤时间(Z=-4.001,P 0.001)、肝功能恢复时间(Z=-1.735,P 0.001)、肝性脑病比例(χ~2=4.114,P=0.043)比较,差异均有统计学意义。多因素logistic回归分析显示,首次肝损伤时间 8周(OR=3.94,95%CI:1.02～15.25,P=0.047)、无症状肝损伤(OR=7.64,95%CI:1.63～35.86,P=0.010)是发生药物性肝损伤的独立危险因素。合并慢性HBV感染(OR=14.42,95%CI:2.66～78.09,P=0.002)、首次肝损伤时间8周(OR=11.97,95%CI:2.03～70.50,P=0.006)是发生肝衰竭的独立危险因素,Alb≥35 g/L(OR=0.07,95%CI:0.01～0.51,P=0.010)是其保护因素。结论抗结核药物会导致严重肝损伤,合并HBV感染、无症状肝损伤、发现肝损伤时间晚、低蛋白会增加严重肝损伤发生风险。定期随访、肝功能监测、适当营养支持和HBV筛查对降低抗结核期间的肝损伤风险具有重要意义。     

军队老年人脑卒中相关危险因素的1比1配对病例对照研究

目的 探讨西安地区军队离退休干部中脑卒中相关危险因素.方法 运用1:1配对病例对照研究的方法,对346例西安地区军队离退休干部的调查资料进行分析,将173例脑卒中患者作为病例组,173例非脑卒中者作为对照组,对照按年龄相差不到1岁、性别和职级相同匹配,采用多因素logistic回归模型分析相关危险因素.结果 病例组患者腰臀比0.953±0.049,对照组0.926±0.060,差异有统计学意义(P＜0.05),与B型血比较,A型血、O型血和AB型血的OR=0.246(95% CI:0.129～0.467)、0R=0.355(95% CI:0.196～0.644)和OR=0.237(95% CI:0.116～0.481).多因素logistic回归分析显示,在调整了收缩压、TC、TG、吸烟、饮酒等因素后,与腰臀比＜0.95者比较,≥0.95者的OR=2.667(95% CI:1.675～4.245),与B型血比较,A型血、O型血和AB型血的OR=0.221(95% CI:0.112～0.434)、OR=0.359(95% CI:0.193～0.670)和OR=0.217(95% CI:0.103～O.456).结论 在该调查人群中血型可能与脑卒中患病相关.     

细胞色素P4501A1、谷胱甘肽转硫酶基因多态性与儿童急性淋巴细胞白血病的相关性研究

目的探讨生物代谢酶细胞色素P4501A1、谷胱甘肽转硫酶M1、T1基因多态性与儿童急性淋巴细胞白血病(ALL)的相关性。方法采用病例对照研究方法,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对89例儿童ALL患儿以及90名健康对照者的CYP1A1 Msp Ⅰ多态(T264C)、GSTMI和GSTT1等基因的多态分布进行分析。结果儿童ALL组的CYP1A1基因Msp Ⅰ多态纯合子突变型(C型)的频率与对照组差异有统计学意义(P0.05),携带纯合子突变型的儿童患ALL的危险度比杂合子突变型(B型)与野生型(A型)儿童的高(OR=1.997,95% CI:1.024～3.896)。GSTM1缺失型分布频率与对照组相比差异有统计学意义(P0.05,OR=2.709,95%CI:1.427～5.146),GSTT1缺失型分布频率与对照组相比差异无统计学意义(P0.05)。同时携带CYPlAl C型、GSTM1、GSTT1缺失型的联合基因型儿童患ALL的风险增加(OR=2.235,95% CI:1.111～4.497)。结论 CYP1A1基因Msp Ⅰ多态纯合子突变型(C型)、GSTM1缺失型与儿童ALL的易感性可能相关,GSTT1缺失型与儿童ALL易感性可能不相关;同时携带CYP1A1 C型与GSTM1、GSTT1缺失基因型可能是儿童ALL发病的易感因素之一。     

Glutathione-S-Transferase GST M1 "Null" Genotype and the Risk of Alcoholic Liver Disease

The present study was conducted to investigate possible association between the occurrence of glutathione-S-transferase GST M1 "null" genotype and alcoholic liver disease (ALD). The "null" genotype indicating absent activity of class p glutathione transferase was assessed in 33 abstainers, 43 moderate alcohol consumers, and 313 heavy alcohol consumers by polymerase chain reaction. The genotypes were compared with occurrence of alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver fibrosis. The "null" genotype was found among 44.7% of patients in the series, with no significant differences between different consumption groups: controls, 36.4%; moderate consumers, 39.5%; and heavy consumers, 46.3%. Occurrence of GST M1 "null" genotype was not associated with occurrence ALD among moderate alcohol consumers. Frequency of the "null" genotype was, however, statistically nearly significantly Cp = 0.07, odds ratio (OR) = 1.751 lower among heavy consumers with normal liver histology than in alcoholics with ALD. Furthermore, when compared with heavy consumers without ALD, the "null" genotype was nearly significantly more frequent among heavy consumers with at least slight liver fibrosis (p = 0.05, OR = 1.8) and statistically significantly more frequent among alcoholics with advanced liver fibrosis (p < 0.025, OR = 2.3). Results of the present Finnish association study suggest that homozygous deletion of the GST M1 gene may indicate increased susceptibility to develop irreversible liver damage in response to the toxic effects of ethanol. Significant association was found between the occurrence of the "null" genotype and the occurrence of alcoholic liver cirrhosis.     

Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity

Gastric marginal zone lymphoma (GMZL) is strongly associated with Helicobacter pylori infection, which induces a chronic inflammatory response. Inflammation can result in DNA damage related to its severity, the cellular antioxidant capacity, and the integrity of DNA repair mechanisms. Interleukin-1 (IL-1) polymorphisms have been shown to be important mediators of inflammation, while glutathione S-transferase GST T1 and GST M1 polymorphisms are believed to affect cellular antioxidant capacity. We aimed to determine whether polymorphisms at the IL-1 and GST T1 and GST M1 loci modulate the risk of developing GMZL. Blood and biopsy samples were obtained for a historical series of 66 GMZL cases, whereas blood samples were available from 163 healthy controls. Genotypes were obtained for GST T1, GST M1, IL-1 RN, and IL-1B-31 using PCR-based techniques. H pylori infection was found in 86.0% of cases, whereas in the control population only 37.4% tested positive. The IL-1 RN 2/2 genotype was significantly associated with risk of GMZL (odds ratio [OR], 5.51; 95% confidence interval [CI] 2.16-14.07), but not the IL-1B-31 genotype. Likewise, the GST T1 null genotype was strongly associated with risk of GMZL (OR, 9.51; 95% CI 4.57-19.81), but not the GST M1 genotype. Evidence was found of effect modification between the IL-1 RN and GST T1 genotypes (P =.02). The combination of the IL-1 RN 2/2 and GST T1 null genotype was most strongly associated with risk of GMZL (OR, 32.29; 95% CI 6.92-150-63). These results support the hypothesis that the risk of developing GMZL is influenced by inter-individual variation in the cellular inflammatory immune responses to H pylori infection, and to antioxidative capacity.     

Associations analysis of GSTM1, T1 and P1 Ile105Val polymorphisms with carpal tunnel syndrome

Oxidative stress was related with carpal tunnel syndrome (CTS). We aimed to clarify the associations between glutathione S-transferase (GST)M1, GSTT1 and GSTP1-Ile105Val polymorphisms and CTS. One hundred-forty patients with CTS and 97 healthy controls were enrolled in this study. Tinel and Phalen signs were noted as positive or negative. Functional and clinical status of patients was evaluated by the Boston Questionnaire. The intensity of hand and/or wrist pain was evaluated on 10 cm visual analog scale (VAS). We applied the polymerase chain reaction (PCR) to determine the polymorphisms of the GSTM1 and GSTT1 and the PCR-restriction fragment length polymorphism method for detecting the GSTP1-Ile105Val polymorphism. The M1 null genotype was significantly higher in patients with CTS compared to healthy controls, and the M1 null genotype seemed to increase the risk of CTS approximately two-fold (P?=?0.011; odds ratio (OR)?=?1.98; 95 % confidence interval (CI) 1.17–3.36). The M1 null, T1 present combined genotype was significantly higher in patients with CTS compared to healthy controls (P?=?0.043); however, it seemed not to increase the risk of CTS (P?=?0.14; OR?=?0.62; 95 % CI 0.33–1.76). We found significantly higher levels of the VAS, Boston Symptom Severity Scale and Phalen sign in patients with the Ile/Val or the Val/Val genotypes compared to those in patients with the Ile/Ile genotype (P?=?0.003, 0.004 and 0.044, respectively). We proposed that genes involved in the protection from oxidative stress may influence the susceptibility, clinical and functional status of CTS. The GSTM1 null genotype may be related with the development of CTS, whereas the Val allele of GSTP1-Ile105Val polymorphism may be associated with worse functional and clinical status in CTS.     

Influence of glutathione S‐transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug‐induced hepatotoxicity in a Caucasian population

Objectives: Genetic variations in enzymes of isoniazid metabolism confer an increased risk for antituberculosis drug‐induced hepatotoxicity in Asian populations. The present study was aimed at investigating the possible association of antituberculosis drug‐induced hepatotoxicity with polymorphisms at the glutathione S‐transferase (GST) gene in a Caucasian population. Methods: A prospective case–control study was nested in a cohort of patients with active tuberculosis who were treated with a combination of isoniazid, rifampicin and pyrazinamide. Cases constituted patients with antituberculosis drug‐induced hepatotoxicity (n=35), and controls constituted patients without any evidence of this complication (n=60). Homozygous null polymorphisms at GST loci M1 and T1 were analysed from genomic DNA from all participants. Results: The GSTT1 homozygous null polymorphism was significantly associated with antituberculosis drug‐induced hepatotoxicity [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.08–6.24, P=0.03]. No significant association was observed between the GSTM1 homozygous null polymorphism and antituberculosis drug‐induced hepatotoxicity (OR 0.73, 95% CI 0.31–1.73, P=0.48). Conclusion: The GSTT1 homozygous null polymorphism may be a risk factor of antituberculosis drug‐induced hepatotoxicity in Caucasians.     

Association of genetic polymorphism of GSTT1, GSTM1 and GSTM3 in COPD patients in a north Indian population

Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). Cigarette smoking is the main etiological factor for decline in lung function in COPD. However, only 10-20% chronic smokers develop symptomatic COPD. Genetic susceptibility to COPD might depend upon the variation of enzyme activities that detoxify cigarette smoke components. We performed a case control study to assess the association of Glutathione- S-transferase T1(GSTT1),Glutathione- S-transferase M1 (GSTM1), and Glutathione-S-transferase M3(GSTM3) common polymorphisms with the susceptibility to COPD patient in a north India population. In the present study, the genotypes of 412 subjects, (204 COPD patients and 208 healthy controls) were analyzed. Statistical analysis revealed that the frequency of homozygous GSTM1 null genotype was found to be significant higher in COPD patients as compared with healthy controls (OR, 2.58; 95% CI, 1.73-3.84; P = 0.001), but there were no significant differences in the distribution of homozygous null GSTT1 and 3-bp deletion polymorphism (rs1799735) in intron 6 variant allele in GSTM3 between COPD patients and healthy controls. Our study results suggest that GSTM1 null polymorphism is associated with genetic susceptibility to COPD. Moreover, we also found association between this polymorphism with pulmonary function test in smokers as well as nonsmokers.     

Association of NAT and GST polymorphisms with non-Hodgkin's lymphoma: a population-based case-control study

Several chemicals have been associated with risk of non-Hodgkin's lymphoma (NHL), many of which are substrates for N-acetyltransferase (NAT) and glutathione S-transferase (GST) enzymes. We investigated the association between polymorphisms in genes coding for these enzymes and NHL risk in a population-based study (389 cases and 535 controls). NAT1 slow genotype was associated with a slightly increased risk in women [odds ratios (OR) = 1.4; 95% confidence interval (CI) = 0.9-2.3], but not in men. NAT2 slow genotype was not associated with risk in either sex. The two slow genotypes of NAT1 and NAT2 combined were associated with a minor increase of risk in women (OR = 1.4; 0.8-2.4). There was no association with the GSTM1 or GSTT1 null genotype in either sex, irrespective of histological subtypes. Individuals with GSTP1 Val homozygotes had non-significant excessive risk of marginal zone lymphoma (OR = 1.8; 0.6-5.1) and 'other' B-cell NHLs (OR = 1.6; 0.7-3.6), but lower risk of diffuse large B-cell lymphoma (OR = 0.2; 0.1-0.96). Risk did not elevate with an increasing number of high-risk GST alleles in either sex. In summary, although NAT1, NAT2, GSTM1, GSTT1, or GSTP1 polymorphisms do not appear to be associated with NHL risk overall, there might be gender-specific and subtype-specific associations that require confirmation.     

GSTM1和T1基因多态性与AFT暴露和肝癌

AIM To explore the relationship between the level of aflatoxin-human serum albumin adducts and polymorphisms of glutathione S-transferase (GST) M1 and T1 and primary liver cancer (PLC).METHODS AFT-albumin adducts were measured by sandwich enzyme-linked immunosorbent assay (ELISA) and genotypes of GST M1 and T1 were determined by PCR.RESULTS Compared with those with non-null genotype of both GST T1 and M1, the odds ratio of developing PLC for those with null genotype of both GST T1 and M1 was 3.11 (95% confidence interval: 1.01-9.98; P=0.029). There was a dose-response relationship between serum level of AFT-albumin adducts and risk of PLC (χ2trend=15.42, P=0.0001). By combined genotype of GST T1 and M1, persons with null genotype of GST T1 and M1 were more likely to have higher AFT-albumin adduct level than those with other genotypes of GST T1 and M1 (F=4.57, P＜0.005). The biological gradients between serum AFT-albumin adducts level and PLC risk were observed to determine whether the persons were of null genotype of GST T1 or M1 or not. The levels of AFT-albumin adduct in Haimen residents in 1992 and 1996 were decreased significantly as against 1987 (F=6.35, P＜0.005).CONCLUSION Exposure to aflatoxin may still be one of risk factors leading to PLC endemic in Haimen population and those with null genotype of GST T1 and M1 may be at greater risk of developing PLC once they are exposed to aflatoxin.     

尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性与抗结核药致肝损害的相关性

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶1A6(UGT1A6)基因多态性与中国唐山地区结核患者抗结核药致肝损害的相关性.方法采用病例对照研究,以抗结核治疗导致肝损害患者202例为病例组,无肝损害者239例为对照组,收集环境因素暴露情况及静脉血.UGT1A6基因多态性分析采用聚合酶链反应限制性片段长度多态方法,利用Hha Ⅰ、Dpn Ⅱ和NsiⅠ内切酶分析其基因多态性,以SPSS13.0软件对各危险因素进行单因素和多因素非条件Logistic回归分析.结果 UGT1A6的19T/G、308C/A和541A/G多态性位点均存在3种基因型,UGT1A6-19T/T、UGT1A6-19T/G和UGT1A6-19G/G在病例组和对照组的频率分别为51.5%、39.6%、8.9%和71.1%、25.5%、3.3%;UGT1A6-308C/C、UGT1A6-308C/A和UGT1A6-308A/A在病例组和对照组的频率分别为52.0%、40.6%、7.4%和79.1%、19.2%、1.7%; UGT1A6-541AA、UGT1A6-541A/G和UGT1A6-541G/G在病例组和对照组的频率分别为57.9%、33.7%、8.4%和79.5%、19.2%、1.3%,两组间差异均有统计学意义(x2值分别为17.956、37.385和24.095,P值均＜0.01).单因素和多因素分析均显示UGT1A6-19T/G、-308C/A、-541A/G 3个位点基因多态性与抗结核药致肝损害的发生有关(P值均＜0.05).结论 UGT1A6基因多态性可能与汉族人抗结核药致肝损害的发病有关,且各基因型存在相互作用.

Abstract：

Objective To investigate the relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury (ADIH). Methods 202 cases and 239 controls were collected and a case-control study was conducted. Information on related risk factors of tuberculosis was collected. The genotypes of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genetic polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism technique (PCRRFLP) in patients received anti-tuberculosis therapy. The Hha Ⅰ, Dpn Ⅱ and NsiⅠenzyme were employed.Univariate and multivariate conditional logistic analyses were conducted using SPSS13.0 for windows software.Results The allele frequency of gene UGT1A6-19T/T, UGT1A6-19T/G, UGT1A6-19G/G, GT1A6-308C/C, UGT1A6-308C/A, UGT1A6-308A/A, UGT1A6-541AA, UGT1A6-541A/G and UGT1A6-541G/G in ADIH group were 51.5%, 39.6%, 8.9%, 52.0%, 40.6%, 7.4%, 57.9%, 33.7%, 8.4% and 71.1%, 25.5%, 3.3%,79.1%, 19.2%, 1.7%, 79.5%, 19.2%, 1.3% in control group, respectively. Univariate analysis demonstrated that the frequency of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genotype in cases were significantly higher than that in controls (P ＜ 0.05). Conclusion A positive association is found between UGT1A6 genotype and the occurrence of ADIH. The synergetic effect is proved on susceptibility to pulmonary tuberculosis between UGT1A6 mutant genotypes.     

Polymorphisms at GSTM1 and GSTT1 gene loci and susceptibility to cervical cancer in Indian population

Multiple allelism at loci encoding detoxifying enzymes is associated with cancer risk. Glutathione S-transferase (GSTs) catalyzes the conjugation of glutathione to numerous potentially genotoxic compounds. This study evaluates the influence of genetic polymorphisms of GST M1 and GST T1 on susceptibility to cervical cancer. A multiplex polymerase chain reaction method was used to detect the presence or absence of the GSTM1 and GSTT1 genes in genomic DNA isolated from cases with cervical cancer (n=142) and normal controls (n=96). The results showed that the frequency of homozygous GSTM1 null genotype was higher in cervical cancer cases (57.0%) as compared to controls (34.4%) and the differences were significant (p<0.05), OR=2.5, 95% CI: 1.4--4.5. The frequency of homozygous GSTT1 null genotype in cancer cases was 19.7% in comparison to 12.5% in controls, however, the difference was not statistically significant (OR=1.7, 95% CI: 0.8-3.8). Significant difference was found between the cases and controls in the distribution of the null genotype of GST M1 in individuals aged above 45 years (p=0.04), but this difference was not significant in individuals aged below 45 years (p=0.06). No significant differences were found in cervical cancer cases and controls when data were analyzed according to age group for GSTT1 null genotype. Further, the combined analysis of both GSTM1 null and GSTT1 null genotypes did not appear to influence the susceptibility to cervical cancer, suggesting that polymorphisms of other detoxifying enzymes may play a significant role in cervical carcinogenesis.