HLA-DP多态性与乙型肝炎病毒感染及其不同结局相关性Meta分析
发布时间：2018-07-15 12:14
【摘要】：[研究背景]乙型肝炎病毒(Hepatitis B virus,HBV)感染是全球范围内严重且值得关注的公共卫生问题之一。据世界卫生组织(World Health Organization,WHO)报道,全世界约有20亿人感染HBV,其中约1/8为慢性HBV感染者。HBV感染可能导致慢性乙型肝炎(chronic hepatitis B,CHB)、肝硬化和肝细胞癌(hepatocellular carcinoma,HCC)的发生。全世界肝硬化和HCC患者中,分别有30%和45%是由HBV感染引起的。我国的HBV感染人数居世界首位,慢性HBV感染者已超过9000万例,其中CHB患者约2000万例。个体感染HBV后临床结局因人而异。研究表明,感染HBV时的年龄是决定HBV感染后病毒持续存在与否的最主要因素。个体感染HBV时年龄越小,越容易形成慢性感染。除年龄外,性别、长期过量饮酒以及合并其他肝炎病毒感染等也与HBV感染慢性化或HBV清除相关。此外,分离分析和双生子研究提示,宿主遗传因素在HBV感染后不同临床转归中发挥至关重要的作用。HBV慢性感染者中,仅有少部分发展成HCC,有HCC家族史的慢性HBV携带者发生HCC的概率是没有HCC家族史HBV慢性携带者的两倍,提示遗传因素在HBV相关HCC发生中起重要作用。全基因组关联研究(genome-wide association study,GWAS)概念提出以前,人们主要利用候选基因关联研究的方法进行HBV慢性感染易感基因的研究,找到了与之相关的若干个遗传易感区域。然而,HBV持续感染的精确发病机制仍不为人知。2009年,日本科学家Kamatani等首次报道了一项日本和泰国人群的HBV感染慢性化GWAS,发现了两个与HBV持续感染显著相关的单核苷酸多态性(single nucleotide polymorphism,SNP)位点,分别为HLA-DP 区域的 rs3077和rs9277535。2011年,同一个研究小组,Mbarek等使用日本人群开展了新一轮的HBV感染慢性化GWAS,结果重复出rs3077和rs9277535与HBV持续感染之间的关联。随后,有关HLA-DP区域的上述两个SNP位点与HBV感染及其不同结局(包括慢性HBV感染、HBV自发清除、CHB活动度、肝硬化和HCC发生)的研究在不同人群中相继开展,但是可能由于样本量小、研究人群的种族差异、表型界定不一致、.SNP的效力较弱等因素的存在,研究结果不尽相同。Meta分析可以通过综合多个同质研究来增大样本量,增加结论的把握度,解决研究结果不一致的问题。本研究在全世界范围内收集符合标准的研究,开展了HLA-DP多态性(rs3077和rs9277535)与乙型肝炎病毒感染及其不同结局相关性Meta分析,对阐明HBV相关肝脏疾病的发病机制和该类疾病的防治具有重要的意义。[目的]探索HLA-DP多态性rs3077和rs9277535位点是否为HBV感染相关肝病遗传易感位点,为阐明HBV相关肝病的发病机制和该类疾病的防治提供一定的科学依据。[方法]运用中文数据库(中国知网、万方和中国生物医学文献数据库等)和英文数据库(PubMed、EMBASE和Cochrane Library等)及相应的中英文检索策略,检索HLA-DP基因2个SNP位点(rs3077和rs9277535)与HBV感染及其不同结局关联研究文献。此外,通过浏览纳入文献的参考文献、综述及Meta分析的参考文献补充相关研究。根据纳入和排除标准筛选最终符合要求的文献。使用Newcastle-Ottawa Scale(NOS)评价纳入研究的质量。两人各自从纳入文献中提取rs3077、rs9277535 2个SNP位点相关研究数据信息。根据病例组和对照组的表型,将每个SNP位点相关数据分为5组:1、慢性HBV感染vs健康对照;2、HBV自发性清除vs慢性HBV感染;3、无症状表面抗原携带者(asymptomatic HBsAg carrier,AsC)vs 有症状 HBV 感染者;4、肝硬化 vs CHB;5、HCC vs HBV携带者。以分别检测rs3077、rs9277535与HBV慢性感染、HBV自发清除、CHB活动度、肝硬化及HCC的发生之间的关联。对于以上任何一组,要求至少存在3项独立来源数据才能进行Meta分析。应用RevMan5.3软件对提取的数据进行统计分析。使用比值比(oddratio,OR)值及其95%可信区间(confidence interval,CI)表示HBV感染及其不同结局与上述2个SNP位点的关联强度。如果数据允许,根据人群种族(亚洲人群和非亚洲人群)进行亚组分析。采用Cochran Q检验来评估研究间可能存在的异质性,P值小于0.1被认为具有显著的异质性。此外,采用I2检验对研究间的异质性进行评价。如果研究间的异质性较大,采用随机效应模型进行合并分析;如果异质性较小,则采用固定效应模型合成统计量。采用去除单项研究法进行敏感性分析。通过制作漏斗图检测是否存在发表偏倚。本项Meta分析中所有数据统计学处理均为双侧。除另做说明,P≤0.05被认为差异具有统计学意义。[结果]本研究共纳入33篇符合纳入标准的文献,NOS评分质量较高。其中,有17篇文献的30组研究探讨rs3077与HBV慢性感染的关联,Meta分析结果提示,rs3077位点A等位基因在亚洲和非亚洲人群中可显著降低HBV慢性感染的风险(OR=0.60,95%CI 0.56-0.63,P0.00001;OR=0.74,95%CI 0.65-0.84,P0.00001)。有17篇文献的33组研究探讨rs9277535与HBV慢性感染的关联,Meta分析结果提示,rs9277535位点A等位基因在亚洲人群中可显著降低 HBV 慢性感染的风险(OR=0.60,95%CI 0.56-0.64,P0.00001)。有 19篇文献的27组研究探讨rs3077与HBV自发清除的关联,Meta分析结果提示,rs3077位点A等位基因在亚洲和非亚洲人群中可显著增加HBV的自发清除(OR=1.50,95%CI 1.37-1.65,P0.00001;OR=1.38,95%CI 1.10-1.72,P=0.005)。有20篇文献的28组研究探讨rs9277535与HBV自发清除的关联,Meta分析结果提示,rs9277535位点A等位基因在亚洲人群中可显著增加HBV的自发清除(OR=1.57,95%CI 1.48-1.67,P0.00001)。有 4 篇文献的 4 组研究探讨 rs3077与CHB活动度的关联,Meta分析结果提示,rs3077可能与CHB活动度无统计学关联(OR=1.09,95%CI0.76-1.57,P=0.63)。有6篇文献的7组研究探讨rs9277535与CHB活动度的关联,Meta分析结果提示,在亚洲人群,rs9277535与CHB活动度无关联(OR=1.04,95%CI 0.93-1.16,P=0.47)。分别有2篇文献的2组研究探讨rs3077、rs9277535与肝硬化发生的关联,因纳入研究的数量较少,故未进行rs3077、rs9277535与肝硬化发生相关性Meta分析。8篇文献的8组研究探讨rs3077与HCC发生的关联,Meta分析结果提示,在亚洲人群,rs3077可能与HCC发生不存在统计学关联(OR=1.01,95%CI 0.93-1.10,P=0.83)。6篇文献的7组研究探讨rs9277535与HCC发生的关联,Meta分析结果提示,在亚洲人群,rs9277535可能与HCC发生无关联(OR= 1.04,95%CI 0.98-1.11,P=0.17)。敏感性分析结果显示,除剔除阿拉伯人的研究后rs3077与CHB活动度关联研究的合并效应发生显著性改变外,其他Meta分析逐一剔除单项研究后合并效应并未发生显著性改变。漏斗图显示,除rs3077、rs9277535与HCC关联研究可能存在发表偏倚,其他均无明显发表偏倚。[结论]HLA-DP基因rs3077和rs9277535位点A等位基因均为HBV感染的保护因素,且显著增加HBV的自发清除;然而,与CHB活动度或HCC的发生不存在统计学关联。
[Abstract]:[background] Hepatitis B virus (HBV) infection is one of the serious and noteworthy public health problems worldwide. According to the WHO (World Health Organization, WHO), about 2 billion people all over the world are infected with HBV, about which 1/8 is a slow HBV infection, which may lead to chronic hepatitis B (chronic hepatitis B). IC hepatitis B, CHB), cirrhosis and hepatocellular carcinoma (hepatocellular carcinoma, HCC). 30% and 45% of the world cirrhosis and HCC patients are caused by HBV infection respectively. The number of HBV infections in our country ranks first in the world, and more than 90 million cases of chronic HBV infection have been found, of which about 20 million cases of CHB patients. The age of HBV infection is the most important factor in determining the persistence of HBV infection. The smaller the age is, the more likely it is to form a chronic infection. Besides age, sex, long-term excessive drinking and other hepatitis virus infection are also associated with the chronicity of HBV infection or HBV clearance. The separation analysis and double birth seed study suggest that the host genetic factor plays a vital role in different clinical outcomes after HBV infection. Only a few of the.HBV chronic infections are developed into HCC. The probability of HCC in chronic HBV carriers with HCC family history is two times less than that of HCC family history HBV chronic carriers, suggesting that the genetic factors are in HBV phase. The genome-wide association study (GWAS) concept is important. Before the concept of association study (GWAS) was proposed, people mainly use the method of candidate gene association to study the susceptibility genes of HBV chronic infection, and find several genetic susceptibility regions related to it. However, the precise pathogenesis of HBV persistent infection, however, has been found. Still unknown.2009, Japanese scientist Kamatani, for the first time, reported a chronicity GWAS of HBV infection in a Japanese and Thailand population, and found two single nucleotide polymorphisms (single nucleotide polymorphism, SNP) associated with persistent HBV infection (single nucleotide polymorphism, SNP), respectively, for rs3077 and rs9277535.2011 years of the HLA-DP region, the same study. The group, Mbarek, and other Japanese people have developed a new round of HBV infection chronicity GWAS, which results in a repeat of the association between rs3077 and rs9277535 and HBV persistent infection. Subsequently, the above two SNP loci in the HLA-DP region and HBV infection and its different outcomes (including chronic HBV infection, HBV spontaneous clearance, CHB activity, cirrhosis and occurrence) The research has been carried out one after another in different population, but it may be due to the small sample size, the racial difference of the population, the inconsistency of phenotypic definition and the weak effect of.SNP, and the different.Meta analysis can increase the sample size by combining multiple homogeneity studies, increase the degree of conclusion and solve the research results. This study collects standard studies all over the world, and develops the correlation of HLA-DP polymorphism (rs3077 and rs9277535) with hepatitis B virus infection and its different outcomes. It is of great significance for clarifying the pathogenesis of HBV related liver diseases and the prevention and treatment of this kind of disease. [Objective] to explore the HLA-DP polymorphism. Whether the rs3077 and rs9277535 loci are the genetic susceptibility loci of HBV infection related liver disease, provide a certain scientific basis for clarifying the pathogenesis of HBV related liver diseases and the prevention and control of this kind of disease. Library etc.) and the corresponding Chinese and English retrieval strategies to retrieve the literature on the association of 2 SNP loci (rs3077 and rs9277535) with HBV infection and its different outcomes in the HLA-DP gene. In addition, the reference literature included in the literature, the review and the reference literature of the Meta analysis are supplemented. The final compliance requirements are based on the inclusion and exclusion criteria. Newcastle-Ottawa Scale (NOS) evaluation was used to evaluate the quality of the study. Two people separately extracted rs3077, rs9277535, 2 SNP loci related data information. According to the phenotype of the case group and the control group, each SNP locus related data was divided into 5 groups: 1, chronic HBV infection vs healthy control; 2, HBV spontaneously clear vs slow. Sexual HBV infection; 3, asymptomatic surface antigen carriers (asymptomatic HBsAg carrier, AsC) vs with symptomatic HBV infection; 4, cirrhosis vs CHB; 5, HCC vs HBV carriers. There are 3 independent source data for Meta analysis. RevMan5.3 software is used to analyze the extracted data. Using the ratio Ratio (oddratio, OR) value and its 95% confidence interval (confidence interval, CI), the correlation intensity of HBV infection and its different outcome with the 2 SNP loci above is indicated. Subgroup analysis of Asian and non Asian people. Cochran Q test was used to assess the possible heterogeneity in the study. The P value was less than 0.1 was considered to have significant heterogeneity. In addition, I2 test was used to evaluate the heterogeneity of the study. If the heterogeneity of the study was larger, a random effect model was used to analyze the heterogeneity; for example If the heterogeneity was small, the fixed effect model was used to synthesize statistics. A single study was used to make a sensitivity analysis. Whether there was a publication bias by making a funnel plot. All data statistics in this Meta analysis were both bilateral. In addition to the other, P < 0.05 was considered statistically significant. [results] this study A total of 33 articles in accordance with the inclusion criteria were included, and the quality of NOS scores was high. Among them, 30 groups of 17 papers studied the association between rs3077 and HBV chronic infection. The Meta analysis showed that the rs3077 locus A alleles could significantly reduce the risk of HBV chronic infection in Asian and non Asian populations (OR=0.60,95%CI 0.56-0.63, P0.00001; OR=0.7). 4,95%CI 0.65-0.84, P0.00001). There were 33 groups of studies in 17 literature to explore the association between rs9277535 and HBV chronic infection. The results of Meta analysis suggested that the rs9277535 locus A alleles could significantly reduce the risk of HBV chronic infection in Asian population (OR=0.60,95%CI 0.56-0.64, P0.00001). 27 groups of studies in 19 literature discussed the spontaneous infection. The results of Meta analysis suggest that the rs3077 locus A alleles can significantly increase the spontaneous clearance of HBV in Asian and non Asian populations (OR=1.50,95%CI 1.37-1.65, P0.00001; OR=1.38,95%CI 1.10-1.72, P=0.005). There are 28 groups of studies in 20 literature to explore the association between rs9277535 and HBV spontaneous clearance. The loci A allele could significantly increase the spontaneous clearance of HBV (OR=1.57,95%CI 1.48-1.67, P0.00001) in the Asian population. 4 groups of studies in 4 literature explored the association between rs3077 and CHB activity. The results of Meta analysis suggested that rs3077 may have no statistical correlation with CHB activity (OR= 1.09,95%CI0.76-1.57,). There were 7 groups of studies in 6 literature. The correlation between rs9277535 and CHB activity was investigated, and the Meta analysis showed that there was no association between rs9277535 and CHB activity in Asian population (OR=1.04,95%CI 0.93-1.16, P=0.47). There were 2 articles in 2 groups to explore the association between rs3077, rs9277535 and the occurrence of cirrhosis, because the number of subjects included in the study was less, so no rs3077, rs9277535 and cirrhosis were carried out. The association between rs3077 and HCC was investigated in 8 groups of.8 literature related to the correlation Meta analysis. The results of Meta analysis suggested that in Asian population, rs3077 may have no statistical association with HCC (OR=1.01,95%CI 0.93-1.10, P=0.83).6 article of 7 studies to explore the association between rs9277535 and occurrence. Group, rs9277535 may have no association with HCC (OR= 1.04,95%CI 0.98-1.11, P=0.17). Sensitivity analysis results show that there is a significant change in the merger effect of the association study of rs3077 and CHB activity except for the study of the Arabs, and the combination effect of other Meta analysis is not significantly changed after the single study is eliminated one by one. In addition to rs3077, there may be a publication bias in the study of the association between rs9277535 and HCC, and there is no obvious bias in others. [conclusion]HLA-DP gene rs3077 and A alleles of rs9277535 site A are all protective factors for HBV infection and significantly increase the spontaneous clearance of HBV; however, there is no statistical association with the occurrence of CHB activity or HCC.
【学位授予单位】：昆明医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62
本文编号：2124038
[Abstract]:[background] Hepatitis B virus (HBV) infection is one of the serious and noteworthy public health problems worldwide. According to the WHO (World Health Organization, WHO), about 2 billion people all over the world are infected with HBV, about which 1/8 is a slow HBV infection, which may lead to chronic hepatitis B (chronic hepatitis B). IC hepatitis B, CHB), cirrhosis and hepatocellular carcinoma (hepatocellular carcinoma, HCC). 30% and 45% of the world cirrhosis and HCC patients are caused by HBV infection respectively. The number of HBV infections in our country ranks first in the world, and more than 90 million cases of chronic HBV infection have been found, of which about 20 million cases of CHB patients. The age of HBV infection is the most important factor in determining the persistence of HBV infection. The smaller the age is, the more likely it is to form a chronic infection. Besides age, sex, long-term excessive drinking and other hepatitis virus infection are also associated with the chronicity of HBV infection or HBV clearance. The separation analysis and double birth seed study suggest that the host genetic factor plays a vital role in different clinical outcomes after HBV infection. Only a few of the.HBV chronic infections are developed into HCC. The probability of HCC in chronic HBV carriers with HCC family history is two times less than that of HCC family history HBV chronic carriers, suggesting that the genetic factors are in HBV phase. The genome-wide association study (GWAS) concept is important. Before the concept of association study (GWAS) was proposed, people mainly use the method of candidate gene association to study the susceptibility genes of HBV chronic infection, and find several genetic susceptibility regions related to it. However, the precise pathogenesis of HBV persistent infection, however, has been found. Still unknown.2009, Japanese scientist Kamatani, for the first time, reported a chronicity GWAS of HBV infection in a Japanese and Thailand population, and found two single nucleotide polymorphisms (single nucleotide polymorphism, SNP) associated with persistent HBV infection (single nucleotide polymorphism, SNP), respectively, for rs3077 and rs9277535.2011 years of the HLA-DP region, the same study. The group, Mbarek, and other Japanese people have developed a new round of HBV infection chronicity GWAS, which results in a repeat of the association between rs3077 and rs9277535 and HBV persistent infection. Subsequently, the above two SNP loci in the HLA-DP region and HBV infection and its different outcomes (including chronic HBV infection, HBV spontaneous clearance, CHB activity, cirrhosis and occurrence) The research has been carried out one after another in different population, but it may be due to the small sample size, the racial difference of the population, the inconsistency of phenotypic definition and the weak effect of.SNP, and the different.Meta analysis can increase the sample size by combining multiple homogeneity studies, increase the degree of conclusion and solve the research results. This study collects standard studies all over the world, and develops the correlation of HLA-DP polymorphism (rs3077 and rs9277535) with hepatitis B virus infection and its different outcomes. It is of great significance for clarifying the pathogenesis of HBV related liver diseases and the prevention and treatment of this kind of disease. [Objective] to explore the HLA-DP polymorphism. Whether the rs3077 and rs9277535 loci are the genetic susceptibility loci of HBV infection related liver disease, provide a certain scientific basis for clarifying the pathogenesis of HBV related liver diseases and the prevention and control of this kind of disease. Library etc.) and the corresponding Chinese and English retrieval strategies to retrieve the literature on the association of 2 SNP loci (rs3077 and rs9277535) with HBV infection and its different outcomes in the HLA-DP gene. In addition, the reference literature included in the literature, the review and the reference literature of the Meta analysis are supplemented. The final compliance requirements are based on the inclusion and exclusion criteria. Newcastle-Ottawa Scale (NOS) evaluation was used to evaluate the quality of the study. Two people separately extracted rs3077, rs9277535, 2 SNP loci related data information. According to the phenotype of the case group and the control group, each SNP locus related data was divided into 5 groups: 1, chronic HBV infection vs healthy control; 2, HBV spontaneously clear vs slow. Sexual HBV infection; 3, asymptomatic surface antigen carriers (asymptomatic HBsAg carrier, AsC) vs with symptomatic HBV infection; 4, cirrhosis vs CHB; 5, HCC vs HBV carriers. There are 3 independent source data for Meta analysis. RevMan5.3 software is used to analyze the extracted data. Using the ratio Ratio (oddratio, OR) value and its 95% confidence interval (confidence interval, CI), the correlation intensity of HBV infection and its different outcome with the 2 SNP loci above is indicated. Subgroup analysis of Asian and non Asian people. Cochran Q test was used to assess the possible heterogeneity in the study. The P value was less than 0.1 was considered to have significant heterogeneity. In addition, I2 test was used to evaluate the heterogeneity of the study. If the heterogeneity of the study was larger, a random effect model was used to analyze the heterogeneity; for example If the heterogeneity was small, the fixed effect model was used to synthesize statistics. A single study was used to make a sensitivity analysis. Whether there was a publication bias by making a funnel plot. All data statistics in this Meta analysis were both bilateral. In addition to the other, P < 0.05 was considered statistically significant. [results] this study A total of 33 articles in accordance with the inclusion criteria were included, and the quality of NOS scores was high. Among them, 30 groups of 17 papers studied the association between rs3077 and HBV chronic infection. The Meta analysis showed that the rs3077 locus A alleles could significantly reduce the risk of HBV chronic infection in Asian and non Asian populations (OR=0.60,95%CI 0.56-0.63, P0.00001; OR=0.7). 4,95%CI 0.65-0.84, P0.00001). There were 33 groups of studies in 17 literature to explore the association between rs9277535 and HBV chronic infection. The results of Meta analysis suggested that the rs9277535 locus A alleles could significantly reduce the risk of HBV chronic infection in Asian population (OR=0.60,95%CI 0.56-0.64, P0.00001). 27 groups of studies in 19 literature discussed the spontaneous infection. The results of Meta analysis suggest that the rs3077 locus A alleles can significantly increase the spontaneous clearance of HBV in Asian and non Asian populations (OR=1.50,95%CI 1.37-1.65, P0.00001; OR=1.38,95%CI 1.10-1.72, P=0.005). There are 28 groups of studies in 20 literature to explore the association between rs9277535 and HBV spontaneous clearance. The loci A allele could significantly increase the spontaneous clearance of HBV (OR=1.57,95%CI 1.48-1.67, P0.00001) in the Asian population. 4 groups of studies in 4 literature explored the association between rs3077 and CHB activity. The results of Meta analysis suggested that rs3077 may have no statistical correlation with CHB activity (OR= 1.09,95%CI0.76-1.57,). There were 7 groups of studies in 6 literature. The correlation between rs9277535 and CHB activity was investigated, and the Meta analysis showed that there was no association between rs9277535 and CHB activity in Asian population (OR=1.04,95%CI 0.93-1.16, P=0.47). There were 2 articles in 2 groups to explore the association between rs3077, rs9277535 and the occurrence of cirrhosis, because the number of subjects included in the study was less, so no rs3077, rs9277535 and cirrhosis were carried out. The association between rs3077 and HCC was investigated in 8 groups of.8 literature related to the correlation Meta analysis. The results of Meta analysis suggested that in Asian population, rs3077 may have no statistical association with HCC (OR=1.01,95%CI 0.93-1.10, P=0.83).6 article of 7 studies to explore the association between rs9277535 and occurrence. Group, rs9277535 may have no association with HCC (OR= 1.04,95%CI 0.98-1.11, P=0.17). Sensitivity analysis results show that there is a significant change in the merger effect of the association study of rs3077 and CHB activity except for the study of the Arabs, and the combination effect of other Meta analysis is not significantly changed after the single study is eliminated one by one. In addition to rs3077, there may be a publication bias in the study of the association between rs9277535 and HCC, and there is no obvious bias in others. [conclusion]HLA-DP gene rs3077 and A alleles of rs9277535 site A are all protective factors for HBV infection and significantly increase the spontaneous clearance of HBV; however, there is no statistical association with the occurrence of CHB activity or HCC.
【学位授予单位】：昆明医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62
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