维生素D代谢通路关键基因遗传变异与乙肝病毒感染结局的关联性研究

发布时间：2018-02-27 16:03

本文关键词： HBV感染维生素D代谢通路遗传变异交互作用　出处：《广东药科大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:1.分析维生素D代谢通路关键基因的遗传变异与乙肝病毒感染结局的关联;2.分析基因-基因、基因-环境交互在乙肝病毒感染进程的作用。方法:采用频数匹配病例-对照研究分析维生素D代谢通路关键基因遗传变异与乙肝病毒感染结局的关联;运用Sequenom MassARRAY分型技术检测维生素D代谢通路关键基因的潜在功能性遗传变异;应用无序多分类Logistic回归分析单个遗传变异与乙肝病毒感染结局的关联性;采用参数法与非参数法相结合的统计分析策略,应用logistic回归模型、多因子降维法系统分析基因-基因、基因-环境交互作用对乙肝病毒感染结局的影响。结果:1.在单遗传变异与乙肝病毒感染结局的关联分析中,多因素Logistic回归模型显示,RXRB的rs2076310与乙肝病毒感染后自限性清除有关,rs2076310 GA基因型、显性模型与HBV感染低风险相关(OR=0.73,95%CI=0.57-0.95;OR=0.73,95%CI=0.57-0.93);CYP24A1的rs2248359 CT基因型、显性模型下可显著增加HBV感染后肝癌的发病风险(OR=1.49,95%CI=1.14-1.96;OR=1.43,95%CI=1.11-1.85);VDR的rs11574012 AG基因型、显性模型与HBV相关肝癌发病风险降低相关(OR=0.62,95%CI=0.44-0.88;OR=0.61,95%CI=0.44-0.85),RXRB的rs2076310的GA基因型、显性模型与HBV相关肝癌发病风险降低存在统计学关联(OR=0.66,95%CI=0.50-0.86;OR=0.66,95%CI=0.51-0.85);VDR的rs11574012位点AG基因型、显性模型下与HBV相关肝癌和慢性HBV感染风险降低相关(OR=0.74,95%CI=0.55-0.99;OR=0.73,95%CI=0.55-0.98),RXRB的rs2076310位点GA基因型、AA基因型和显性模型中也与HBV相关肝癌和慢性HBV感染风险降低相关(OR=0.71,95%CI=0.57-0.88;OR=0.66,95%CI=0.47-0.92;OR=0.70,95%CI=0.57-0.86)。2.单倍体分析发现VDR基因构建的TCTCATG单体型显著降低慢性HBV感染后发生肝癌的风险(OR=0.64,95%CI=0.43-0.96);TCTCGTG单体型与HBV相关肝癌风险降低相关(OR=0.63,95%CI=0.41-0.95)。3.两因素水平的基因-环境交互分析表明VDR rs11574012与吸烟之间存在显著的交互作用。与自限性清除者相比,携带rs11574012的AA基因型有恶性肿瘤家族史者HBV感染的风险比AG+GG基因型无恶性肿瘤家族史者降低(OR=0.34,95%CI=0.20-0.58),且rs2248359与恶性肿瘤家族史存在显著的相乘交互作用(Pmult=0.043)。与慢性HBV感染者相比,携带rs11574012的AA基因型吸烟者HBV相关肝癌风险是AG+GG基因型非吸烟者的4.91倍(95%CI=2.91-8.29),且该位点与吸烟的相乘交互具有统计学意义(Pmult=0.018);携带rs2248359的CT+TT基因型有恶性肿瘤家族史者HBV相关肝癌风险是CC基因型无恶性肿瘤家族史者的8.17倍(95%CI=4.61-14.47),且rs2248359与恶性肿瘤家族史存在显著的相乘交互作用(Pmult=0.008)。结论:1.VDR rs11574012和RXRB rs2076310是乙肝病毒感染结局的易感性位点,CYP24A1 rs2248359的突变等位基因T可增加HBV相关肝癌发病风险。2.VDR rs11574012与恶性肿瘤家族史之间的交互在乙肝病毒感染后达到自限清除HBV过程起重要作用。rs11574012与吸烟之间以及rs2248359与恶性肿瘤家族史之间的交互在乙肝病毒感染后进展为肝癌中起重要作用。
[Abstract]:Objective: to correlate genetic variation analysis of 1. vitamin D metabolic pathway key genes of hepatitis B virus infection and outcome; 2. analysis of gene gene and gene environment interaction in hepatitis B virus infection process. Methods: a comparative study of vitamin D metabolic pathway key genes genetic variation and association with outcomes of hepatitis B virus infection frequency matched case the potential function; using Sequenom MassARRAY typing technique for the detection of vitamin D metabolic pathway key genes of genetic variation; application of Logistic regression analysis of individual genetic variation and association with outcomes of hepatitis B virus sense; using statistical parametric method and non parametric method of combining analysis strategy, application of logistic regression model, analysis of gene gene reduced dimension method of multi factor, gene environment interaction on hepatitis B virus infection outcome. Results: 1. in the single and the genetic variation of hepatitis B The outcome of the viral infection correlation analysis, multivariate Logistic regression model showed that rs2076310 and RXRB of hepatitis B virus infection after self limiting clearance of rs2076310, GA genotype, low risk dominant model with HBV infection (OR=0.73,95%CI=0.57-0.95; OR=0.73,95%CI= 0.57-0.93); rs2248359 CT CYP24A1 genotype, the risk increased significantly under the dominant model HBV after infection of hepatocellular carcinoma (OR=1.49,95%CI=1.14-1.96; OR=1.43,95%CI=1.11-1.85); rs11574012 AG VDR genotype, dominant model associated with HBV was associated with reduced risk of liver cancer (OR=0.62,95%CI=0.44-0.88; OR=0.61,95%CI=0.44-0.85), the GA genotype of RXRB rs2076310, reduce the dominant model HBV associated with the risk of liver cancer were related (OR=0.66,95%CI=0.50-0.86; OR=0.66,95%CI=0.51-0.85); rs11574012 AG gene VDR, the dominant model and HBV related hepatocellular carcinoma and slow HBV infection risk reduction (OR=0.74,95%CI=0.55-0.99; OR=0.73,95%CI=0.55-0.98), rs2076310 GA genotype RXRB, AA genotype and dominant model is also associated with HBV liver cancer and chronic HBV infection risk reduction (OR=0.71,95%CI=0.57-0.88; OR=0.66,95%CI= 0.47-0.92; OR=0.70,95%CI=0.57-0.86).2. haplotype analysis found that HCC risk VDR gene TCTCATG haplotype was significantly decreased in chronic after HBV infection (OR=0.64,95%CI=0.43-0.96); TCTCGTG haplotype was associated with reduced risk of liver cancer associated with HBV (OR=0.63,95%CI= 0.41-0.95.3.) two factors and levels of gene environment interaction analysis showed that there was significant interaction between VDR rs11574012 and smoking. Compared with self limiting clearance, AA genotype with rs11574012 family history of malignancy the risk of HBV infection than AG+GG genotype had no family history of malignant tumor and decreased (O R=0.34,95%CI=0.20-0.58), there was significant interaction and multiplication of rs2248359 and family history of malignant tumor (Pmult=0.043). Compared with chronic HBV infection, AA genotype of HBV related liver cancer risk smokers carrying rs11574012 AG+GG genotype was 4.91 times for non smokers (95%CI= 2.91-8.29), and the polymorphism and smoking multiplicative interaction was statistically significant (Pmult=0.018); CT+TT genotype with rs2248359 family history of malignancy of HBV related liver cancer risk is 8.17 times of the CC genotype had no family history of malignant tumor (95%CI=4.61-14.47), there was significant interaction and multiplication of rs2248359 and family history of malignant tumor (Pmult=0.008). Conclusion: 1.VDR rs11574012 and RXRB rs2076310 is a susceptibility locus for hepatitis B the outcome of viral infection, CYP24A1 rs2248359 mutant allele T can increase the risk of liver cancer related HBV.2.VDR rs11574012 and malignant tumor The interaction between family history plays an important role in the process of self limiting clearance of HBV after HBV infection. The interaction between.Rs11574012 and smoking and the family history of rs2248359 and malignant tumor play an important role in the progression of HBV infection to HCC.

【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62

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