【摘要】：[研究背景]乙型肝炎病毒(Hepatitis B virus,HBV)感染是全球范圍內(nèi)嚴(yán)重且值得關(guān)注的公共衛(wèi)生問題之一。據(jù)世界衛(wèi)生組織(World Health Organization,WHO)報(bào)道,全世界約有20億人感染HBV,其中約1/8為慢性HBV感染者。HBV感染可能導(dǎo)致慢性乙型肝炎(chronic hepatitis B,CHB)、肝硬化和肝細(xì)胞癌(hepatocellular carcinoma,HCC)的發(fā)生。全世界肝硬化和HCC患者中,分別有30%和45%是由HBV感染引起的。我國(guó)的HBV感染人數(shù)居世界首位,慢性HBV感染者已超過9000萬例,其中CHB患者約2000萬例。個(gè)體感染HBV后臨床結(jié)局因人而異。研究表明,感染HBV時(shí)的年齡是決定HBV感染后病毒持續(xù)存在與否的最主要因素。個(gè)體感染HBV時(shí)年齡越小,越容易形成慢性感染。除年齡外,性別、長(zhǎng)期過量飲酒以及合并其他肝炎病毒感染等也與HBV感染慢性化或HBV清除相關(guān)。此外,分離分析和雙生子研究提示,宿主遺傳因素在HBV感染后不同臨床轉(zhuǎn)歸中發(fā)揮至關(guān)重要的作用。HBV慢性感染者中,僅有少部分發(fā)展成HCC,有HCC家族史的慢性HBV攜帶者發(fā)生HCC的概率是沒有HCC家族史HBV慢性攜帶者的兩倍,提示遺傳因素在HBV相關(guān)HCC發(fā)生中起重要作用。全基因組關(guān)聯(lián)研究(genome-wide association study,GWAS)概念提出以前,人們主要利用候選基因關(guān)聯(lián)研究的方法進(jìn)行HBV慢性感染易感基因的研究,找到了與之相關(guān)的若干個(gè)遺傳易感區(qū)域。然而,HBV持續(xù)感染的精確發(fā)病機(jī)制仍不為人知。2009年,日本科學(xué)家Kamatani等首次報(bào)道了一項(xiàng)日本和泰國(guó)人群的HBV感染慢性化GWAS,發(fā)現(xiàn)了兩個(gè)與HBV持續(xù)感染顯著相關(guān)的單核苷酸多態(tài)性(single nucleotide polymorphism,SNP)位點(diǎn),分別為HLA-DP 區(qū)域的 rs3077和rs9277535。2011年,同一個(gè)研究小組,Mbarek等使用日本人群開展了新一輪的HBV感染慢性化GWAS,結(jié)果重復(fù)出rs3077和rs9277535與HBV持續(xù)感染之間的關(guān)聯(lián)。隨后,有關(guān)HLA-DP區(qū)域的上述兩個(gè)SNP位點(diǎn)與HBV感染及其不同結(jié)局(包括慢性HBV感染、HBV自發(fā)清除、CHB活動(dòng)度、肝硬化和HCC發(fā)生)的研究在不同人群中相繼開展,但是可能由于樣本量小、研究人群的種族差異、表型界定不一致、.SNP的效力較弱等因素的存在,研究結(jié)果不盡相同。Meta分析可以通過綜合多個(gè)同質(zhì)研究來增大樣本量,增加結(jié)論的把握度,解決研究結(jié)果不一致的問題。本研究在全世界范圍內(nèi)收集符合標(biāo)準(zhǔn)的研究,開展了HLA-DP多態(tài)性(rs3077和rs9277535)與乙型肝炎病毒感染及其不同結(jié)局相關(guān)性Meta分析,對(duì)闡明HBV相關(guān)肝臟疾病的發(fā)病機(jī)制和該類疾病的防治具有重要的意義。[目的]探索HLA-DP多態(tài)性rs3077和rs9277535位點(diǎn)是否為HBV感染相關(guān)肝病遺傳易感位點(diǎn),為闡明HBV相關(guān)肝病的發(fā)病機(jī)制和該類疾病的防治提供一定的科學(xué)依據(jù)。[方法]運(yùn)用中文數(shù)據(jù)庫(中國(guó)知網(wǎng)、萬方和中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫等)和英文數(shù)據(jù)庫(PubMed、EMBASE和Cochrane Library等)及相應(yīng)的中英文檢索策略,檢索HLA-DP基因2個(gè)SNP位點(diǎn)(rs3077和rs9277535)與HBV感染及其不同結(jié)局關(guān)聯(lián)研究文獻(xiàn)。此外,通過瀏覽納入文獻(xiàn)的參考文獻(xiàn)、綜述及Meta分析的參考文獻(xiàn)補(bǔ)充相關(guān)研究。根據(jù)納入和排除標(biāo)準(zhǔn)篩選最終符合要求的文獻(xiàn)。使用Newcastle-Ottawa Scale(NOS)評(píng)價(jià)納入研究的質(zhì)量。兩人各自從納入文獻(xiàn)中提取rs3077、rs9277535 2個(gè)SNP位點(diǎn)相關(guān)研究數(shù)據(jù)信息。根據(jù)病例組和對(duì)照組的表型,將每個(gè)SNP位點(diǎn)相關(guān)數(shù)據(jù)分為5組:1、慢性HBV感染vs健康對(duì)照;2、HBV自發(fā)性清除vs慢性HBV感染;3、無癥狀表面抗原攜帶者(asymptomatic HBsAg carrier,AsC)vs 有癥狀 HBV 感染者;4、肝硬化 vs CHB;5、HCC vs HBV攜帶者。以分別檢測(cè)rs3077、rs9277535與HBV慢性感染、HBV自發(fā)清除、CHB活動(dòng)度、肝硬化及HCC的發(fā)生之間的關(guān)聯(lián)。對(duì)于以上任何一組,要求至少存在3項(xiàng)獨(dú)立來源數(shù)據(jù)才能進(jìn)行Meta分析。應(yīng)用RevMan5.3軟件對(duì)提取的數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析。使用比值比(oddratio,OR)值及其95%可信區(qū)間(confidence interval,CI)表示HBV感染及其不同結(jié)局與上述2個(gè)SNP位點(diǎn)的關(guān)聯(lián)強(qiáng)度。如果數(shù)據(jù)允許,根據(jù)人群種族(亞洲人群和非亞洲人群)進(jìn)行亞組分析。采用Cochran Q檢驗(yàn)來評(píng)估研究間可能存在的異質(zhì)性,P值小于0.1被認(rèn)為具有顯著的異質(zhì)性。此外,采用I2檢驗(yàn)對(duì)研究間的異質(zhì)性進(jìn)行評(píng)價(jià)。如果研究間的異質(zhì)性較大,采用隨機(jī)效應(yīng)模型進(jìn)行合并分析;如果異質(zhì)性較小,則采用固定效應(yīng)模型合成統(tǒng)計(jì)量。采用去除單項(xiàng)研究法進(jìn)行敏感性分析。通過制作漏斗圖檢測(cè)是否存在發(fā)表偏倚。本項(xiàng)Meta分析中所有數(shù)據(jù)統(tǒng)計(jì)學(xué)處理均為雙側(cè)。除另做說明,P≤0.05被認(rèn)為差異具有統(tǒng)計(jì)學(xué)意義。[結(jié)果]本研究共納入33篇符合納入標(biāo)準(zhǔn)的文獻(xiàn),NOS評(píng)分質(zhì)量較高。其中,有17篇文獻(xiàn)的30組研究探討rs3077與HBV慢性感染的關(guān)聯(lián),Meta分析結(jié)果提示,rs3077位點(diǎn)A等位基因在亞洲和非亞洲人群中可顯著降低HBV慢性感染的風(fēng)險(xiǎn)(OR=0.60,95%CI 0.56-0.63,P0.00001;OR=0.74,95%CI 0.65-0.84,P0.00001)。有17篇文獻(xiàn)的33組研究探討rs9277535與HBV慢性感染的關(guān)聯(lián),Meta分析結(jié)果提示,rs9277535位點(diǎn)A等位基因在亞洲人群中可顯著降低 HBV 慢性感染的風(fēng)險(xiǎn)(OR=0.60,95%CI 0.56-0.64,P0.00001)。有 19篇文獻(xiàn)的27組研究探討rs3077與HBV自發(fā)清除的關(guān)聯(lián),Meta分析結(jié)果提示,rs3077位點(diǎn)A等位基因在亞洲和非亞洲人群中可顯著增加HBV的自發(fā)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篇文獻(xiàn)的28組研究探討rs9277535與HBV自發(fā)清除的關(guān)聯(lián),Meta分析結(jié)果提示,rs9277535位點(diǎn)A等位基因在亞洲人群中可顯著增加HBV的自發(fā)清除(OR=1.57,95%CI 1.48-1.67,P0.00001)。有 4 篇文獻(xiàn)的 4 組研究探討 rs3077與CHB活動(dòng)度的關(guān)聯(lián),Meta分析結(jié)果提示,rs3077可能與CHB活動(dòng)度無統(tǒng)計(jì)學(xué)關(guān)聯(lián)(OR=1.09,95%CI0.76-1.57,P=0.63)。有6篇文獻(xiàn)的7組研究探討rs9277535與CHB活動(dòng)度的關(guān)聯(lián),Meta分析結(jié)果提示,在亞洲人群,rs9277535與CHB活動(dòng)度無關(guān)聯(lián)(OR=1.04,95%CI 0.93-1.16,P=0.47)。分別有2篇文獻(xiàn)的2組研究探討rs3077、rs9277535與肝硬化發(fā)生的關(guān)聯(lián),因納入研究的數(shù)量較少,故未進(jìn)行rs3077、rs9277535與肝硬化發(fā)生相關(guān)性Meta分析。8篇文獻(xiàn)的8組研究探討rs3077與HCC發(fā)生的關(guān)聯(lián),Meta分析結(jié)果提示,在亞洲人群,rs3077可能與HCC發(fā)生不存在統(tǒng)計(jì)學(xué)關(guān)聯(lián)(OR=1.01,95%CI 0.93-1.10,P=0.83)。6篇文獻(xiàn)的7組研究探討rs9277535與HCC發(fā)生的關(guān)聯(lián),Meta分析結(jié)果提示,在亞洲人群,rs9277535可能與HCC發(fā)生無關(guān)聯(lián)(OR= 1.04,95%CI 0.98-1.11,P=0.17)。敏感性分析結(jié)果顯示,除剔除阿拉伯人的研究后rs3077與CHB活動(dòng)度關(guān)聯(lián)研究的合并效應(yīng)發(fā)生顯著性改變外,其他Meta分析逐一剔除單項(xiàng)研究后合并效應(yīng)并未發(fā)生顯著性改變。漏斗圖顯示,除rs3077、rs9277535與HCC關(guān)聯(lián)研究可能存在發(fā)表偏倚,其他均無明顯發(fā)表偏倚。[結(jié)論]HLA-DP基因rs3077和rs9277535位點(diǎn)A等位基因均為HBV感染的保護(hù)因素,且顯著增加HBV的自發(fā)清除;然而,與CHB活動(dòng)度或HCC的發(fā)生不存在統(tǒng)計(jì)學(xué)關(guān)聯(lián)。
[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.
【學(xué)位授予單位】：昆明醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R512.62

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