【作者】 范桂玲；

【导师】 贾崇奇；

【作者基本信息】 山东大学 ， 流行病与卫生统计学， 2008， 硕士

【摘要】 研究背景慢性肝炎是严重危害人类身体健康、影响人类期望寿命和生存质量的疾病,是目前我国及众多国家的重要疾病负担之一。因此,深入探讨慢性肝炎的发病机理,对该病的防治与诊治具有重要的指导意义。慢性肝炎是受遗传与环境因素共同作用的多因子疾病,基因-基因及基因-环境因素交互作用在该病的发病中具有重要的作用。近年来随着人类基因组计划的迅速发展和分子生物学技术的应用,从基因水平阐明慢性肝炎的发病机制成为医学界关注的热点。慢性乙型肝炎是慢性肝炎的最常见的主要原因,酒精摄入也是重要的危险因素之一。众多研究显示,酒精损害与慢性肝炎密切相关,而乙醇脱氢酶2(ADH2)基因Arg47His变异又是影响酒精代谢的一个重要因素。因此该变异与慢性肝炎之间的关系如何是一个很值得深入探讨的问题。有研究表明,该变异与酒精依赖以及肝硬化、肝癌密切相关。然而关于ADH2基因Arg47His变异与慢性肝炎的关系,以及该变异与其它危险因素之间的交互作用对慢性肝炎患病的影响如何,目前国内外尚未见报道。研究目的1.探讨ADH2基因Arg47His变异与慢性肝炎之间的关系。2.探讨ADH2基因Arg47His变异与其它危险因素之间在慢性肝炎发病中的交互作用。研究方法采用以医院为基础的病例对照研究设计,以明确诊断的慢性肝炎患者为研究对象。选择济南市传染病医院确诊的252例汉族慢性肝炎患者作为病例组,223名汉族正常人为对照组。运用PCR-RFLP方法检测ADH2基因Arg47His变异。运用F检验比较计量资料各组之间的均数差异;运用x~2检验分析计数资料在各组之间的频数分布差异;运用单因素及多因素Logistic回归分析ADH2基因Arg47His变异与慢性肝炎之间的关系。ADH2基因Arg47His变异与其它因素之间的交互作用采用病例对照以及无对照病例研究,并用Logistic回归予以分析。研究结果1.性别、年龄、吸烟在慢性肝炎组和对照组之间差异无统计学意义(P＞0.05)。饮酒、肝炎家族史在两组之间差异有统计学意义(P＜0.05)。饮酒及肝炎家族史阳性比率慢性肝炎组显著高于对照组。2.ADH2基因Arg47His变异基因型频率慢性肝炎组(GG、GA、AA频率分别为13.1%、48.4%、38.5%)与对照组(GG、GA、AA频率分别为7.2%、42.6%、50.2%)比较有显著性差异(P=0.014)。ADH2基因Arg47His变异等位基因频率慢性肝炎组(G、A等位基因频率分别为37.3%、62.7%)与对照组(G、A等位基因频率分别为28.5%、71.5%)比较也有显著差异(P=0.005)。野生型基因型与等位基因频率慢性肝炎组显著高于对照组。3.ADH2基因Arg47His变异与慢性肝炎的关系以突变型纯合子AA为参照组,以logistic回归模型分析ADH2基因Arg47His变异与慢性肝炎的关系。调整潜在混在因素前,GA与GG基因型的OR分别为1.48(95%CI:1.01-2.17)与2.38(95%CI:1.24-4.59)。调整性别、年龄、吸烟、饮酒、肝炎家族史后,其OR分别为1.46(95%CI:0.97-2.19)与2.51(95%CI:1.25-5.02)。4.ADH2基因Arg47His变异与饮酒之间交互作用分析本分析采用病例对照设计,将基因型分为AA+GA与GG两水平,以logistic回归模型分析其与饮酒之间对慢性肝炎患病的交互作用。结果显示,无论潜在的混杂变量调整前后,两因素同时存在的效应皆大于各因素单独存在时效应之和。调整潜在的混杂因素前,效应指数(S)为1.90,交互效应超额相对危险度(RERI)为1.62,归因交互效应百分比(AP)为36.64%。调整性别、年龄、吸烟、肝炎家族史后,S为2.08,RERI为2.27,AP为42.22%。5.ADH2基因Arg47His变异与乙肝病毒复制水平之间交互作用分析本分析采用无对照病例研究。将基因型分为AA+GA与GG两水平,并作为因变量,以乙肝病毒复制水平为自变量,用logistic回归模型予以分析,并将性别、年龄、吸烟、饮酒、Alt、Ast、Tbil、Dbil、A、G、Alp、Ggt作为潜在的危险因素予以调整。结果显示,ADH2基因Arg47His变异与乙肝病毒复制水平之间存在明显的相乘模型交互作用,其OR值为3.22,(P=0.07)。以AA、GA与GG各基因型作为因变量,并以AA基因型作为参照组,以乙肝病毒复制水平为自变量,用多状态logistic回归模型予以分析,并将性别、年龄、吸烟、饮酒、Alt、Ast、Tbil、Dbil、A、G、Alp、Ggt作为潜在的危险因素予以调整。GA基因型与乙肝病毒复制水平之间无明显的相乘模型交互作用,其OR为1.10,(P=0.81);但是GG基因型与乙肝病毒复制水平之间存在明显的相乘模型交互作用,其OR为3.51,(P=0.06)。结论1.吸烟、性别、年龄与慢性肝炎无显著相关。而饮酒及肝炎家族史阳性与慢性肝炎显著相关。2.ADH2基因Arg47His变异野生型基因类型可能是中国汉族慢性肝炎发病的重要危险因素之一。3.ADH2基因Arg47His变异野生型基因类型与饮酒之间在慢性肝炎的发病中存在明显的交互作用。4.ADH2基因Arg47His变异野生型基因类型与乙肝病毒复制水平之间在慢性肝炎的发病中也存在明显的交互作用。意义与创新:本研究运用病例对照及无对照病例研究设计,在国内外首次比较全面地分析了ADH2基因Arg47His变异与慢性肝炎的关系,以及该变异与其它危险因素之间的交互作用在慢性肝炎患病中的效应。研究结果不但为进一步进行同类研究提供了参考基础,而且对慢性肝炎高危人群的确定以及慢性肝炎的防制具有一定的指导意义。更多还原

【Abstract】 BackgroundChronic hepatitis B disease can do great harm to human health and quality of life and affect people’s life expectancy.It is also an important cause of death and burden of disease in China and many other countries.So to further the study on the pathogenesis of chronic hepatitis B is very important for the prevention and control of the disease.Chronic hepatitis B disease is the most common cause of chronic hepatitis,and alcohol is one of the major risks to it.Chronic hepatitis B is a multi-factorial disease, which is related to both the genetic and environmental factors.Gene has an important role in chronic hepatitis B incidence.There are research papers that indicate geneenvironment interaction makes great contribution to the risk of chronic hepatitis B.With the advance of Human Genome Project and application of molecular biologic technics,it has become more and more popular in medical fields to clarify the pathogenesis of chronic hepatitis B at gene level.There is much research that indicates a close association between alcohol’s damage to liver and chronic hepatitis.Arg47His Mutation in alcohol dehydrogenase (ADH)2 Gene is an important factor that affects alcohol metabolism.So the association between Arg47His Mutation in ADH2 Gene and chronic hepatitis needs be explored further.There is some research that mutation has much to do with alcohol dependence,liver Cirrhosis and liver cancer.However,reports are extremely rare presently on the association between Arg47His Mutation in ADH2 Gene and chronic hepatitis and the interaction between the mutation and other risk factors on chronic hepatitis B.Objective1.To explore the association between Arg47His Mutation in ADH2 Gene and chronic hepatitis B.2.To explore and assess the interaction effect between Arg47His Mutation in ADH2 Gene and other risk factors on chronic hepatitis B and the dose-effect relationship of the interaction.MethodsA hospital-based case-control study was conducted.A total of 252 diagnosed chronic hepatitis B patients in Jinan Infectious Disease hospital and 223 health adults were recruited as study subjects.A PCR-RFLP was performed to detect Arg47His Mutation in ADH2 Gene.Univariate test and multiple logistic regression models were used to analyze the association between Arg47His Mutation in ADH2 Gene and chronic hepatitis B.Results1.There was no significant difference between chronic hepatitis B group and control group in terms of sex,age and smoking factors.But there was significant difference between two groups in terms of alcohol drinking and family history of chronic hepatitis B.2.The difference of the frequencies for ADH2 genotypes between chronic hepatitis B group(GG,GA,AA were 13.1%,48.4%,38.5%,respectively) and the control group(GG,GA,AA were 17.2%,42.6%,50.2%,respectively) was significant (P=0.014);The frequency of G allele in hepatitis B group(37.3%) was significant higher than that in the control group(28.5%)(P=0.005). 3.Compared with the carriers of homozygotes of the AA allele as the reference, the crude ORs with 95%CIs in the parentheses for the chronic hepatitis B were that 1.48(1.01-2.17)for the heterozygous carriers,and 2.38(1.24-4.59)for the carriers of homozygotes of the GG allele,respectively.The multivariate adjusted ORs were 1.46(0.97-2.19),and 2.51(1.25-5.02)for the heterozygous carriers,and for the carriers of homozygotes of the GG allele,respectively.4.There was interaction between Arg47His mutation in ADH2 Gene and alcohol drinking on the chronic hepatitis B.Based on the ORs,the measures of interaction as departure from additivity were as follows:the synergy index(S)was 1.90,the relative excess risk due to interaction(RERI)was 1.62,and the attributable proportion due to interaction(AP)was 36.64%.After the adjustment for the potential confounders,S was 2.08,RERI was 2.27,and AP was 42.22%.5.Using the case-only study,the multinomial logistic regression analysis indicated that there was also interaction as departure from multiplicative between Arg47His mutation in ADH2 Gene and hepatitis B virus reproduction on the chronic hepatitis B.The multivariate adjusted ORs were 1.10(95%CI:0.51-2.38)for the heterozygous carriers and 3.51(95%CI:0.93-13.32)for the carriers of homozygotes of the GG allele,respectively.Conclusions1.There is no significant association between age,sex,smoking and chronic hepatitis B.However,alcohol drinking and family history of hepatitis B were significant associated with chronic hepatitis B.2.Arg47His mutation in ADH2 Gene might serve as one of major risk factors to chronic hepatitis B in the Han nationality of China3.There was interaction as departure from additivity between Arg47His mutation in ADH2 Gene and alcohol drinking on the chronic hepatitis B.4.There was also interaction as departure from multiplicative between Arg47His mutation in ADH2 Gene and hepatitis B virus reproduction on the chronic hepatitis B.更多还原