ADH2、ALDH2基因多态性及饮酒和胃癌关联的研究

[目的]探讨乙醇脱氢酶2(ADH2)、乙醛脱氢酶2(ALDH2)基因多态性及饮酒和胃癌的联系。[方法]采用病例对照研究的方法,利用变性高效液相色谱法(DHPLC)检测常熟市201例男性原发性胃癌患者和对照组ADH2、ALDH2基因型,结合饮酒因素分析其在胃癌发生中的作用。[结果]与携带ADH2(A/A)或ALDH2(G/G)基因型者相比,其它基因型并不增加患胃癌的危险性(P0.05),结合ADH2、ALDH2基因多态性及饮酒因素发现,即使饮酒量超过1.5 kg.年饮酒者任何基因型组合和不饮酒者携带ADH2(A/A)或ALDH2(G/G)基因型者相比,患胃癌的危险性并未增加(P0.05)。[结论]ADH2、ALDH2基因多态性与胃癌易感性无关。     

ALDH2和CYP2E1基因多态性及饮酒习惯与肝细胞癌易感性的关系

目的研究乙醛脱氢酶2(ALDH2)和细胞色素P4502E1(CYP2E1)基因多态性与饮酒因素交互作用在广西原发性肝细胞癌发生中的作用。方法对广西壮族自治区300例肝细胞癌和292例正常对照进行流行病学调查研究,并用PCR-RFLP方法检测ALDH2和CYP2E1基因型。结果病例和对照组中ALDH2和CYP2E1变异基因型携带者分别占50.3%、48.0%和32.3%、32.9%(P0.05)。饮酒频度每周≥3次(高频饮酒)且携带变异基因ALDH2和CYP2E1者发生肝癌的危险度分别是饮酒频度每周3次(低频饮酒)且携带野生基因型者的3.334倍(95%CI=1.746～6.406)和1.803倍(95%CI=0.974～3.336),同时携带两变异基因型者患肝癌风险为1.200倍(95%CI=0.730～1.972),且饮酒增加两变异基因型携带者的肝癌发病风险(OR=1.816,95%CI=0.985～3.348)。结论单一ALDH2或CYP2E1基因型与肝细胞癌易感性无关;但高频饮酒且携带变异基因ALDH2或CYP2E1者患肝癌风险增加,且两变异基因型单倍体增加肝癌发病风险。提示乙醇在增加肝癌发病风险的过程中存在基因-环境和基因-基因相互作用。     

亚甲基四氢叶酸还原酶A1298C多态性与胃癌易感性的关系

[目的]探讨亚甲基四氢叶酸还原酶(MTHFR)基因多态性与胃癌易感性的关系及与环境因素的交互作用。[方法]收集南京市原发性胃癌患者169例,采用1:1病例-对照研究方法随机选取非消化系统疾病、非肿瘤病人为对照,进行流行病学调查,取外周血,采用限制性片段长度多态性方法(PCR-RFLP)分析研究对象MTHFR1298位点的多态性,并分析MTHFR1298基因多态性与烟酒嗜好在胃癌发生中的交互作用。[结果]MTHFR1298C等位基因在病例组与对照组中的频率分别为21.6%和13.0%,差异具有显著性(χ2=8.693,P=0.003,OR=1.841,95%CI=1.223~2.772)。携带MTHFR1298A/C基因型者患胃癌危险性增高(χ2=10.994,P=0.001,OR=2.160,95%CI=1.365~3.419),携带A/C基因型同时又吸烟者患胃癌的危险性是A/A型不吸烟者的3.289倍(χ2=10.002,P=0.002,95%CI=1.573~6.880),携带A/C基因型不饮酒者患胃癌的危险性是携带A/A基因型不饮酒者的2.726倍(χ2=12.459,P<0.001,95%CI=1.562~4.758),同时携带A/C基因型、吸烟、饮酒者患胃癌的危险性是携带A/A基因型、不吸烟、不饮酒者的2.394倍(χ2=3.933,P=0.047,95%CI=1.010~5.672)。[结论]MTHFR1298A/C基因型可增加胃癌易感性,并与吸烟、饮酒间存在交互作用。     

山东地区NAT2基因多态性与乳腺癌易感性的研究

[目的]研究NAT2基因多态性与乳腺癌易感性的关系。[方法]采用1︰1配对病例-对照研究,对山东地区100例乳腺癌患者和100例健康对照者采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP),检测NAT2基因多态性,分析NAT2基因多态性与乳腺癌易感性之间的关系。[结果]携带NAT2*5B等位基因者患乳腺癌危险性增加(OR=2.38,95%CI=1.54～3.67);慢基因型者患乳腺癌的危险性是快基因型者2.28倍(OR=2.28,95%CI=1.12～4.63);是中间基因型者2.14倍(OR=2.14,95%CI=1.08～4.24);慢型乙酰化患乳腺癌的危险性是快型乙酰化的2.11倍(OR=2.11,95%CI=1.15～3.88)。[结论]NAT2基因多态性在乳腺癌的遗传发病机制中起重要作用,携带NAT2*5B等位基因、慢基因型及慢型乙酰化能增加患乳腺癌的易感性。     

修复酶基因多态性与食管癌易感性关系

目的研究DNA修复基因-着色性干皮病基因A（XPA）、着色性干皮病基因D（XPD）、X线修复交叉互补基因1（XRCC1）和X线修复交叉互补基因3（XRCC3）多态性与食管癌易感性的关系.方法通过1：1配对的病例-对照研究方法收集样本106对,应用PCR-限制性片断长度多态性（PCR-RFLP）技术检测样本的基因型,比较不同基因型与食管癌易感性的关系.结果携带XPA G/G基因型的个体与携带A/A基因型者相比,可降低患食管癌的危险性（OR=0.4737,95%CI=0.2280～0.9839）;食管癌组中,携带XRCC1 399Gln/Gln的个体数高于对照组,其患食管癌的危险性是对照人群的3倍（OR=3.447,95%CI=1.078～11.026,P=0.029）.结论 DNA修复基因XPA 23位和XRCC1399位多态可能在食管癌的发生中起一定作用.     

青海藏族人群ADH3、ALDH2基因多态性及其与饮酒行为的关系

目的 了解青海藏族男性乙醇脱氢酶3(ADH3)和乙醛脱氢酶2(ALDH2)基因多态性分布及其与饮酒行为的关系.方法 采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对ADH3和ALDH2基因型进行检测;采用回顾性问卷调查研究对象的饮酒行为.结果 等位基因ADH3*2和ALDH2*2在藏族人群中的比例分别为7.79％和22.21％;不饮酒组中等位基因ALDH2*2、ADH3*1频率高于饮酒者;危险饮酒组中等位基因ALDH2*2、ADH3*1频率低于安全饮酒者.结论 ADH3、ALDH2基因与青海藏族男性人群饮酒行为有关.     

DNA双链断裂修复基因NBS 1多态性与肺癌易感性的关联研究

目的 探讨DNA双链断裂修复基因NBS1多态性与肺癌遗传易感性的关系.方法 采用病例对照设计,应用PCR-RFLP技术检测575例患者和575名对照的NBS1基因多态.结果 对照组和病例组NBS1 rs1805794的C/C、C/G、G/G基因型频率分别为25.9%、51.8%、22.3%和20.5%、52.3%、27.1%,两组分布差异有统计学意义(χ~2=6.38,P=0.04),携带C/G+G/G基因型个体患肺癌的风险是携带C/C基因型者的1.46倍(OR=1.46,95%C1:1.09～1.97).对照组和病例组NBS1 rs2735383的G/G、G/C、C/C基因型频率分别为37.9%、47.0%、15.1%和35.5%、48.5%、16.0%,两组分布差异无统计学意义(χ~2=0.75,P=0.69).携带Hap4-GC单体型或Hap4/Hap2单体型对者患肺癌的风险增加,OR值分别为1.70(95%CI:1.24～2.31)和1.75(95%CI:1.11～2.76),NBS1基因多态与吸烟有联合作用(P＜0.05).结论 NBS1 rs1805794 G/G基因型可能是肺癌的易感基因型,rs1805794和rs2735383位点构建的Hap4-GC单体型及Hap4/Hap2单体型对可能是肺癌的易感单体型和单体型对.     

MPO、NQO1、GSTP1和UGT1A6基因多态与慢性苯中毒遗传易感性关系

目的探讨MPO、NQO1、GSTP1和UGT1A6基因多态与慢性苯中毒易感性的关系。方法采用病例-对照研究,以268名苯中毒工人为病例组,268名接触苯而没有中毒表现的工人为对照组。应用TaqManPCR分析技术判定MPO(rs7208693),NQO1(rs1800566),GSTP1(rs947894)和UGT1A6(rs6759892,rs1105879,rs4124874,rs3755319,rs887829和rs4148323)基因型。结果携带GSTP1基因rs947894G等位基因个体患慢性苯中毒的危险性比AA基因型个体降低0.657倍(95%CI0.434~0.994,P=0.046);携带MPO基因rs7208693A等位基因人群中,UGT1 A6 rs6759892G等位基因个体发生慢性苯中毒的危险性是TT基因型的2.702倍(P=0.024),UGT1 A6 rs1105879C等位基因个体发生慢性苯中毒的危险性是TT型的2.619倍(P=0.035)。在饮酒人群中,携带NQO1基因rs1800566TT基因型个体慢性苯中毒的发病风险较携带CC和CT基因型个体增加9.000倍(95%CI1.460~55.478,P=0.021);在吸烟人群中,带NQO1基因rs1800566TT基因型个体慢性苯中毒的发病风险较携带CC和CT基因型个体增加7.000倍(95%CI1.555~31.575,P=0.012)。单倍型分析显示,本人群携带UGT1A6基因TACGGG单倍型个体慢性苯中毒的发病风险是携带TAATGG单倍型个体的1.446倍(OR=1.446,95%CI1.005~2.080,P=0.046)。结论同时携带MPO基因rs7208693A和UGT1A6基因rs6759892G或rs1105879C等位基因型个体对苯中毒易感;携带NQO1基因rs1800566TT基因型且同时吸烟或饮酒的个体对苯中毒易感;携带UGT1A6基因TAATGG单倍型个体可增加慢性苯中毒的发病风险;GSTP1基因多态与慢性苯中毒遗传易感性的关系仍需进一步研究。     

ALDH2基因多态性与男性饮酒行为关系的分子流行病学研究

目的 探讨乙醛脱氢酶基因(acetaldehyde dehydrogenase gene 2,ALDH2)多态性与男性饮酒行为的关系.方法 采用TaqMan对823名正常男性ALDH2的9个标签单核苷酸多态性位点(single-nucleotide polymorphism,SNP)进行分型,使用Logistic回归分析基因型与饮酒行为的关系.结果 调整年龄、受教育、婚姻、收入和吸烟后,5个SNP与饮酒行为的关联具有统计学意义(rs671 (G＞ A),OR=0.35,95％ CI:0.27～0.45,P＜0.001;rs2283354(G＞A),OR =1.61,95％ CI:1.26 ～2.05,P＜0.001;rs4767939(G＞A),OR=1.46,95％ CI:1.01 ～2.11,P=0.042;rs79073142(T＞C),OR=1.71,95％ CI:1.37 ～2.14,P＜0.001;rs2106696(A ＞T),OR=1.75,95％ CI:1.40 ～2.19,P＜0.001).携带危险等位基因个数越多,发生饮酒行为的可能性越高(趋势性P值＜0.001).SNP两两之间的交互效应没有统计学意义.结论 ALDH2基因多态性可影响中国男性饮酒行为.     

XRCC1基因和ERCC2基因多态与胃癌的研究

目的探讨DNA损伤修复相关基因XRCC1 Arg399Gln和ERCC2 Lys751Gln多态单独或联合与胃癌发病风险的关系。方法采用病例-对照研究设计,利用聚合酶链反应(PCR)结合限制性片段长度多态性(RFLP)方法,对300例病例和300例对照进行基因型分析,采用多因素logistic回归模型因素分析各基因型以及基因之间交互作用与胃癌发病风险的关系。结果 XRCC1 Arg399Gln多态与胃癌发病风险无关;与携带751 Lys/Lys基因型的个体相比,携带751Gln/Gln基因型的个体胃癌发病的风险增加(OR=2.39,95%CI:1.47~3.89;P0.001)。XRCC1基因型和ERCC2基因型存在交互作用,携带XRCC1 399Arg/Gln和ERCC2 751Gln/Gln基因型者患胃癌的风险增加(OR=4.63,95%CI:2.11~10.16;P0.001),携带XRCC1 399Gln/Gln和ERCC2 751 Lys/Gln基因型者患胃癌的风险增加(OR=2.77,95%CI:1.48~5.19;P=0.001)。结论 XRCC1 Arg399Gln和ERCC2 Lys751Gln多态可能是胃癌的遗传易感因素。     

ADH1B与ALDH-2基因多态性与中国人群食管癌发病风险的Meta分析

目的探讨中国人乙醇脱氢酶1B(ADH1B)和乙醛脱氢酶-2(ALDH-2)的基因多态性与食管癌发病风险的关系。方法检索中外文数据库,获得有关ADH1B和ALDH-2位点的多态性与食管癌发病风险的病例-对照研究资料,对各位点以及与饮酒的交互作用进行Meta分析,得到合并的OR值及其95%CI。结果等位基因ADH1B*1和ALDH-2*2可增加食管癌的发病风险。基因型ADH1B*1/*2和ADH1B*1/*1的OR值分别为1.24(95%CI 1.10-1.41)和3.05(95%CI 1.94-4.77);基因型ALDH-2*1/*2和ALDH-2*2/*2的OR值分别为1.6(95%CI 1.01-2.03)和0.77(95%CI 0.28-2.09)。在饮酒人群中,与基因型ADH1B*2/*2相比,ADH1B*1/*2+*2/*2的OR=3.13(95%CI 2.17-4.51);与基因型ALDH-2*1/*1相比,ALDH-2*1/*2+*2/*2的OR=4.12(95%CI 1.98-8.56)。结论在中国人群中,等位基因ADH1B*1和ALDH-2*2均能增加食管癌患病的风险,且饮酒可以增加这一风险。     

乙醛脱氢酶2与饮酒和HBsAg致肝癌交互作用

目的：研究乙醛脱氢酶-2(ALDH2)基因多态性与饮酒习惯和HbsAg致肝癌的交互作用。方法：选择88例新发肝癌病人按性别、年龄和居住地进行1：1配对流行病学调查。病例和对照均采集静脉血，用PCR-RFLP法检测研究对象的ALDH2基因型，用ELISA法检测血中乙型肝火病毒表面抗原（HbsAg）。结果：病例组（36.40％）与对照组（35.22％）ALDH2变异基因型（G/L L/L）的分布频率无显性差异；但HbsAg阳性率病例组（72.73％）显高于对照组（22.73％）；大量饮酒、HbsAg阳性与ALDH变异基因型的交互作用指数分别为0.8320和0.6634。 结论：乙醛脱氢酶2变异基因型与大量饮酒和HbsAg阳性致肝癌发生有显的交互作用。携带ALDH2变异基因型大量饮酒将显增加患肝癌的危险性。     

Association between smoking, acetaldehyde dehydrogenase-2 1-1 status, and alcohol drinking among Taiwanese polyvinyl chloride workers

To study the factors affecting alcohol consumption among Taiwanese workers, we conducted an investigation of the association between alcohol drinking and smoking, aldehyde dehydrogenase-2 (ALDH2) status, alcohol dehydrogenase-2 (ADH2) status, any history of abnormal liver function, and hepatitis B and C viral infection. The subjects included 207 male workers who had been followed-up with respect to liver function periodically since 1992. Information relating to current alcohol consumption and smoking habits was obtained by an interviewer-administered questionnaire in 1996, and any history of liver function and hepatitis B and C virus infection was obtained from previous medical surveillance. Genotypes of ALDH2 and ADH2 were determined by polymerase chain reaction/restriction fragment polymorphism assay. Results have revealed that smoking and ALDH2 1-1 status were associated with current alcohol consumption (respectively: odds ratio, 23.3; P < 0.01 and odds ratio, 14.5; P < 0.05). Neither a history of abnormal liver function nor a history of hepatitis B and/or C infection was associated with current alcohol consumption. It seems that only those with ALDH2 1-1 who are smokers consume alcohol. We conclude that smoking and inherited ALDH2 1-1 are the most important determinants of alcohol consumption. In addition to the medical advice of physicians in their yearly health check-ups, worksite health-promotion programs based on both alcohol consumption habits and smoking cessation should be instituted forthwith, particularly for those who demonstrate the potential for developing liver damage.     

Gene-environmental interactions in alcohol-related health problems--contributions of molecular biology to behavior modifications

High alcohol sensitivity among Asians is mainly due to a genetic polymorphism in the low Km aldehyde dehydrogenase (ALDH2) gene. Strong correlations between the ALDH2 genotype and alcohol sensitivity or alcohol drinking habits have been reported. Another prevalent polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) among Asians appears to modify skin flushing reactions after exposure to ethanol but does not influence alcohol drinking behavior. Both the ADH2 and ALDH2 genotypes have been significantly correlated with the risk of alcoholism. In a Japanese occupational population, a gene-environment interaction of the ALDH2 genotype and daily hassles scores for development of problem drinking behavior was observed. Habitual drinkers with the ALDH2*1/*2 genotype had higher frequencies of sister-chromatid exchange in cultured lymphocytes and higher 8-OHdG levels in polymorphonuclear leukocytes than those with the ALDH2*1/*1 genotype. Alcoholics and heavy drinkers with the ALDH2*1/*2 genotype have been shown to have significantly elevated risks for esophageal and multiple cancers in upper digestive organs than those with the ALDH2*1/*1 genotype. In Japan, bronchial asthma patients with the ALDH2*1/*2 genotype have been shown to have a significantly elevated risk for experiencing alcohol-induced asthma compared with the ALDH2*1/*1 genotype. Providing services to determine these genotypes would be of great help for each individual to make a plan for tailor-made health promotion.     

Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review

Possession of the fast metabolizing alleles for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer. To examine this association, the authors undertook a Human Genome Epidemiology review on these three genes and a pooled analysis of published studies on ADH1C. The majority of Asians had the fast ADH1B*2 and ADH1C*1 alleles, while the majority of Caucasians had the slow ADH1B*1/1 and ADH1C*1/2 genotypes. The ALDH2*2 null allele was frequently observed among Asians, though it was rarely observed in other populations. In a pooled analysis of data from seven case-control studies with a total of 1,325 cases and 1,760 controls, an increased risk of head and neck cancer was not observed for the ADH1C*1/2 genotype (odds ratio = 1.00, 95% confidence interval: 0.81, 1.23) or the ADH1C*1/1 genotype (odds ratio = 1.14, 95% confidence interval: 0.92, 1.41). Increased relative risks of head and neck cancer were reported for the ADH1B*1/1 and ALDH2*1/2 genotypes in several studies. Recommendations for future studies include larger sample sizes and incorporation of relevant ADH and ALDH genes simultaneously, as well as other genes. These considerations suggest the potential for the organization of a consortium of investigators conducting studies in this field.     

相对的两对引物-聚合酶链反应技术在乙醛脱氢酶-2基因分型中的应用

目的 了解乙醛脱氢酶-2(ALDH2)基因型在广西壮族和汉族健康人群中的分布及其对饮酒行为的影响.方法 分别采用相对的两对引物一聚合酶链反应(PCR-CTPP)和聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP)检测193名汉族和88名壮族成人ALDH2基因型,问卷调查其饮酒行为.结果 壮族和汉族人群ALDH21基因频率分别为0.511、0.489,ALDH22基因频率分别为0.508、0.492,差异无统计学意义(χ2=0.001,P＞0.05).PCR-CTPP的分型结果与PCR-RFLP结果相符.高频饮酒且携带ALDH21纯合基因型者在汉族和壮族各占15.67%和35.59%,差异有统计学意义(χ2=5.800,P=0.016).结论 广西汉族和壮族人群中ALDH2基因型频率分布无差异,不同民族人群的ALDH2遗传型可能对其饮酒行为有影响.     

CD55启动子区rs2564978多态性影响肝癌遗传易感性

目的 探讨CD55在肝癌中表达及预后影响,并分析CD55 rs2564978遗传变异对肝癌遗传易感性的影响。方法 通过数据库GEO和Kaplan-Meier plotter分析CD55在肝癌中表达及预后影响;随机抽取中国北方汉族334例肝癌患者和940例健康对照进行成组设计病例对照研究。PCR-RFLP法进行基因多态检测,卡方检验比较分类变量的分布,非条件logistic校正混杂因素,OR及其95%CI评价各基因型与肝癌易感性的关系。结果 CD55在肝癌组织中表达上调（t=-3.130,P=0.003）且CD55高表达与携带肝炎病毒的肝癌患者不良预后相关（HR=2.28,95%CI:1.10～4.72,P=0.022）。与TT基因型携带者相比,CT基因型（OR=1.45,95%CI:1.08～1.96,P=0.014）与CC基因型（OR=1.55,95%CI:1.08～2.22,P=0.018）携带者肝癌易感性均上升。分层分析显示,rs2564978 T>C变异增加男性肝癌易感性（OR=1.58,95%CI:1.03～2.41,P=0.036）;高年龄组（>60岁）CC携带者具有更高的肝癌易感性（OR=2.46,95%CI:1.35～4.47,P=0.003）;吸烟人群和饮酒人群中,CC携带者肝癌易感性上升（吸烟:OR=1.91,95%CI:1.02～3.58,P=0.042;饮酒:OR=2.37,95%CI:1.20～4.67,P=0.013）。结论 CD55在肝癌组织中表达上调并导致肝癌患者预后不良;CD55启动子区rs2564978遗传变异可能与肝癌易感性相关。     

Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers

AIMS: The objective was to clarify the effect of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) genotypes on the diabetic risk in Japanese workers. METHODS: At the time of mandatory health checkup, the ADH2 and ALDH2 genotypes, as well as fasting plasma glucose (FPG) levels, body mass index (BMI), smoking habit, and weekly alcohol intake, were examined in 492 men and 183 women working at motor vehicle dealerships. RESULTS: In using two-way analysis of variance to manipulate ADH2 and ALDH2 genotypes and alcohol intake (>70 g/week for men and >35 g/week for women), the FPG level after the adjustment for age, BMI, smoking habit, and another genotype was significantly higher in the men with ADH2*1/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH2*1/1 genotype. In contrast, the women with ALDH2*1/1 genotype had significantly lower FPG levels than those with the other genotypes, but there was no significant difference in the FPG level between the women with and without ADH2*1/1 genotype. Also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the women. CONCLUSIONS: These findings suggest that genotypes of ADH2 and ALDH2 can modify the diabetic risk, irrespective of amounts of alcohol consumed. Also, there may be sex differences in the effect of these enzyme genotypes on glucose metabolism.