發(fā)布時間：2018-02-27 16:03

  本文關(guān)鍵詞： HBV感染 維生素D代謝通路 遺傳變異 交互作用　出處：《廣東藥科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:1.分析維生素D代謝通路關(guān)鍵基因的遺傳變異與乙肝病毒感染結(jié)局的關(guān)聯(lián);2.分析基因-基因、基因-環(huán)境交互在乙肝病毒感染進(jìn)程的作用。方法:采用頻數(shù)匹配病例-對照研究分析維生素D代謝通路關(guān)鍵基因遺傳變異與乙肝病毒感染結(jié)局的關(guān)聯(lián);運用Sequenom MassARRAY分型技術(shù)檢測維生素D代謝通路關(guān)鍵基因的潛在功能性遺傳變異;應(yīng)用無序多分類Logistic回歸分析單個遺傳變異與乙肝病毒感染結(jié)局的關(guān)聯(lián)性;采用參數(shù)法與非參數(shù)法相結(jié)合的統(tǒng)計分析策略,應(yīng)用logistic回歸模型、多因子降維法系統(tǒng)分析基因-基因、基因-環(huán)境交互作用對乙肝病毒感染結(jié)局的影響。結(jié)果:1.在單遺傳變異與乙肝病毒感染結(jié)局的關(guān)聯(lián)分析中,多因素Logistic回歸模型顯示,RXRB的rs2076310與乙肝病毒感染后自限性清除有關(guān),rs2076310 GA基因型、顯性模型與HBV感染低風(fēng)險相關(guān)(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、顯性模型下可顯著增加HBV感染后肝癌的發(fā)病風(fēng)險(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、顯性模型與HBV相關(guān)肝癌發(fā)病風(fēng)險降低相關(guān)(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、顯性模型與HBV相關(guān)肝癌發(fā)病風(fēng)險降低存在統(tǒng)計學(xué)關(guān)聯(lián)(OR=0.66,95%CI=0.50-0.86;OR=0.66,95%CI=0.51-0.85);VDR的rs11574012位點AG基因型、顯性模型下與HBV相關(guān)肝癌和慢性HBV感染風(fēng)險降低相關(guān)(OR=0.74,95%CI=0.55-0.99;OR=0.73,95%CI=0.55-0.98),RXRB的rs2076310位點GA基因型、AA基因型和顯性模型中也與HBV相關(guān)肝癌和慢性HBV感染風(fēng)險降低相關(guān)(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.單倍體分析發(fā)現(xiàn)VDR基因構(gòu)建的TCTCATG單體型顯著降低慢性HBV感染后發(fā)生肝癌的風(fēng)險(OR=0.64,95%CI=0.43-0.96);TCTCGTG單體型與HBV相關(guān)肝癌風(fēng)險降低相關(guān)(OR=0.63,95%CI=0.41-0.95)。3.兩因素水平的基因-環(huán)境交互分析表明VDR rs11574012與吸煙之間存在顯著的交互作用。與自限性清除者相比,攜帶rs11574012的AA基因型有惡性腫瘤家族史者HBV感染的風(fēng)險比AG+GG基因型無惡性腫瘤家族史者降低(OR=0.34,95%CI=0.20-0.58),且rs2248359與惡性腫瘤家族史存在顯著的相乘交互作用(Pmult=0.043)。與慢性HBV感染者相比,攜帶rs11574012的AA基因型吸煙者HBV相關(guān)肝癌風(fēng)險是AG+GG基因型非吸煙者的4.91倍(95%CI=2.91-8.29),且該位點與吸煙的相乘交互具有統(tǒng)計學(xué)意義(Pmult=0.018);攜帶rs2248359的CT+TT基因型有惡性腫瘤家族史者HBV相關(guān)肝癌風(fēng)險是CC基因型無惡性腫瘤家族史者的8.17倍(95%CI=4.61-14.47),且rs2248359與惡性腫瘤家族史存在顯著的相乘交互作用(Pmult=0.008)。結(jié)論:1.VDR rs11574012和RXRB rs2076310是乙肝病毒感染結(jié)局的易感性位點,CYP24A1 rs2248359的突變等位基因T可增加HBV相關(guān)肝癌發(fā)病風(fēng)險。2.VDR rs11574012與惡性腫瘤家族史之間的交互在乙肝病毒感染后達(dá)到自限清除HBV過程起重要作用。rs11574012與吸煙之間以及rs2248359與惡性腫瘤家族史之間的交互在乙肝病毒感染后進(jìn)展為肝癌中起重要作用。
[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.

【學(xué)位授予單位】：廣東藥科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R512.62

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本文編號：1543353