【作者】 里进；

【导师】 林菊生；

【作者基本信息】 华中科技大学 ， 分子生物学与生物化学， 2012， 博士

【摘要】 [研究目的]HLA-DP(Human leukocyte antigen DP)多态性已经在日本和泰国人群中证明与HBV(hepatitis B virus)感染有关。我们的目的是检验这种关联性是否能在中国汉族人群中重复。[研究方法]采用Tap-man MGB探针法,将HLA-DPA1 rs2395309和HLA-DPB1 rs9277535 (HLA-DP基因座上最强关联的两SNPs)在三个独立的汉族人群中分型,包括2805例乙肝感染者和1796例对照。通过SPSS17.0软件对分型结果进行关联分析。通过Arlequin 3.5和haploview 4.2软件分析人群的异质性及单体型。[实验结果]通过logistic回归分析,两SNPs与南北汉族HBV的感染和感染后清除均呈显著相关(rs2395309 P=0.021-3.36×10-8；rs9277535 P=8.37×10-3-2.68×10-10)。此外,HLA-DPA1 rs2395309和HLA-DPB1 rs9277535的基因型分布在中国南北汉族人群中存在着很大差异。通过使用HBV无症状携带者作为对照,我们的实验发现HLA-DP两SNPs的变异与HBV感染后恶性化转归并无关联性(南方人群rs2395309P=0.305-0.822,rs9277535 P=0.163-0.881；北方人群rs2395309 P=0.097-0.697,rs9277535 P=0.198-0.615)[实验结论]HLA-DP基因座上的两SNPs (rs2395309, rs9277535)在中国南北汉族人群中与HBV的感染和感染后清除均呈显著相关,但不与HBV恶性化转归有关。简而言之,携带HLA-DP保护等位基因的人群不易感染HBV,感染后也易清除。[研究目的]为了更有力的支持第一部分的结论,检索最新的HLA-DP研究成果,我们对HLA-DP多态性与HBV相关性肝病的研究文献进行了一个Meta分析。[研究方法]采用系统查询的方法检索PubMe、google学术、Scirus、中国知网、万方等国内外数据库。设定文献纳入和排除标准,将提取到的数据输入统计学软件Stata中,进行同质性检验、构建固定效应模型／随机效应模型、检测出版偏倚等Meta分析步骤。[实验结果]对所检索到的23篇文献按纳入和剔除标准进行筛选,最终得到10篇可用于汇总的文献。根据不同的疾病表现对本Meta分析分为三类：1.HLA-DP与HBV清除的Meta分析。其结果取得了最好的荟萃效应,rs9277535、rs2395309两位点合并后均不存在异质性(P>0.05)；2.HLA-DP与HBV肝癌Meta的分析。结果与第一部分一样,均是阴性,但荟萃文献中有不同观念；3. HLA-DP与HBV感染的Meta分析。其结果中存在很大的异质性,rs9277535固定效应模型时12=69.8%,P=0.002,随机效应模型时12=63.9%,P=0.007。[实验结论]通过Meta分析,我们进一步确认HLA-DP rs9277535、rs2395309与HBV感染和感染后清除有着密切关系,而HLA-DP上的某些位点可能是HBV肝癌的易感SNPs,但其确切关系需要更大规模研究的证实。更多还原

【Abstract】 Background and purpose:Human leukocyte antigen DP(HLA-DP) locus has been reported to be associated with hepatitis B virus (HBV) infection in populations of Japan and Thailand. We aimed to examine whether the association can be replicated in Han Chinese.Methods:By using Tap-man MGB probe, two HLA-DP variants rs2395309 and rs9277535 (the most strongly associated SNPs from each HLA-DP locus) were genotyped in three independent Han cohorts consisting of 2805 cases and 1796 controls. The SPSS 17.0 Software was analyzed for the genotyped results. By using Arlequin 3.5 and haploview 4.2 software, we got the informations of population heterogeneity and haplotypes.Results:By using logistic regression analysis, these two SNPs in the HLA-DPA1 and HLA-DPB1 genes were significantly associated with HBV infection in Han Chinese populations (P=0.021-3.36×10-8at rs2395309; P=8.37×10-3-2.68×l0-10at rs9277535). In addition, the genotype distributions of both sites (rs2395309 and rs9277535) were clearly different between southern and northern Chinese population (P=8.95×10-5 at rs2395309; P =1.64×10-9 at rs9277535). By using asymptomatic HBV carrier as control group, our study showed that there were no associations of two HLA-DP variants with HBV progression (P =0.305～0.822 and 0.163～0.881 in southern Chinese population, respectively; P= 0.097～0.697 and 0.198～0.615 in northern Chinese population, respectively).Conclusion:Our results confirmed that two SNPs (rs2395309 and rs9277535) in the HLA-DP loci were strongly associated with HBV infection in southern and northern Han Chinese populations, but not with HBV progression.In a word, HLA-DP polymorphisms only participated in HBV infection, but did not participate in the carcinogenesis of HBV. Background and purpose:In order to support for the conclusion of the first part and get the latest paper, we performed a Meta-analysis for the HLA-DP polymorphism with HBV-related liver disease.Methods:After setting criteria, we retrieval the related papers by using Pubmed, google academic, Scirus and other literature database. The data, which is extracted from papers, were put into the Stata statistical software. Meta-analysis include Homogeneity test, building a fixed effects model/random effects model, detecting publication bias and other steps.Results:According to the screening criteria, we choose 10 papers from the initial 23. On the base of the different disease, the Meta-analysis were divided into three categories. First, the Meta-analysis of the relationship between HLA-DP and HBV clearance achieved the best results, and the two SNPs meet heterogeneity (P＞0.05). Second, the results of HLA-DP and HBV-related liver cancer were negative, like the conclusion of the first part. Third, there was great heterogeneous in the Meta-analysis of HLA-DP and HBV infection. In rs9277535, the heterogeneity is I2=69.8%, P=0.002 in fixed effect model, and I2=63.9%, P=0.007 in random effects model.Conclusion:By Meta-analysis, we further confirmed that the strong associations between HLA-DP rs9277535, rs2395309 and HBV infections/Clear. Besides, some sites in the HLA-DP may be susceptible to HBV-related liver cancer, but the relationships require more study.更多还原