IL-10启动子区SNPs与乙型肝炎病毒感染的相关研究
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摘要
HBV感染是急慢性肝炎的主要原因,其感染机体后引起疾病的进程及转归有很大差别,与病毒本身因素、宿主免疫和遗传因素以及治疗干预因素等密切相关。
IL-10在机体的免疫调节中起着重要作用,IL-10的分泌水平,在很大程度上取决于遗传因素,而其表达水平的改变,直接影响病毒性肝炎的易感性、严重程度、以及对治疗的敏感性等。由于IL-10启动子区的SNP能够直接影响其表达水平,因而IL-10启动子区位置的SNP是进行研究的热点。
在进行IL-10基因多态性与HBV感染的相关研究方面,国内外不同学者的研究结果不尽相同,本研究设立患者组、自限性感染组和正常对照组三组,采用病例-对照群体关联分析的方法,通过PCR-RFLP检测手段,对研究对象IL-10-592和1082位点的SNP进行检测,并进行基因分型,观察不同基因型在不同组别中的分布情况,最后运用统计学手段进行相关性分析。结果显示,IL-10-592位点在患者组、自限性感染组和正常对照组均存在AA、AC、CC 3种基因型,根据不同基因型在三组中的分布情况,不能排除IL-10-592多态性与HBV感染后转归可能存在相关性。IL-10-1082位点在患者组和自限性感染组均存在AA、AG、GG 3种基因型,正常对照组中未检测到GG基因型。根据不同基因型在三组中的分布情况,认为IL-10-1082多态性可能与HBV感染后转归无相关性。IL-10-592多态性与乙肝患者血清转氨酶水平、血清病毒载量和肝脏病理改变无相关性。IL-10-592多态性与阿德福韦酯敏感性相关分析提示,与用药后转氨酶恢复程度可能有相关性,与DNA动态变化无相关性。值得扩大样本量进一步研究。
为有关SNP的研究提供了一些新的思路。
Hepatitis B virus (HBV) infection can cause disease. The proceeding of disease and turnover show great difference. One can show with asymptomatic HBV carriers to cryptic hepatitis, acute hepatitis, chronic hepatitis, liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the interventional factors. IL-10 possesses extensive immunizing vigour. It is a immunoregulation cytokine with immunological inhibition and immunostimulation dual effects. It playes central action in body’s immunoregulation. So the change of IL-10 level, can affect susceptibility to virus hepatitis, severity and sensibility to therapy, and so on. The secretary level of IL-10 is determined by genetic factor at a large degree. IL-10 promoter takes responsibility in combination with regulatory factor for gene expression and thereby promoter SNPs can affect transcription and expression of IL-10 gene directly. SNP has hereditary stability, it has been extensively utilized as a kind of genetic marker. As for HBV infection, SNPs in promoter region of IL-10 are the hot spot of study. Not only can they affect expressed regulation of IL-10 vivo alone, but also they can control the change of IL-10 level as linked pattern, that is to shape different haplotype. So the study on gene polymorphism in promoter region of IL-10 in patients with hepatitis B has significance. This study applied case-control association analysis, aimed at identifying the correlation between gene polymorphism in IL-10promoter and turnover after HBV infection, severity of hepatitis B, and patients’sensitivity to adefovir. So can expect to clear the pathogenesy of hepatitis B and provide necessary theoretical evidence for more effective preventing and treating HBV infection.
Subjects were divided in to three groups as patients, self limiting infection and normal control. All subjects in these three groups were all Han people in the northern part of China, and they could match each other in sex and age. The SNPs of IL-10-592 and -1082 were detected and genotyping was performed using PCR-RFLP. And observing the distribution of different genotype in different groups, finally carrying out association analysis with statistically means.
The following are the major results obtained in this study.
1. The genotypic distributions of IL-10-592 and IL-10-1082 SNP in all subjects were not deviated from the H-W equilibrium (P>0.05).
2. AA,AC and CC genotypes of IL-10-592 locus were detected in patients,self limiting infection and normal control groups. Mutant gene frequency was found to be 55.56%,64.67% and 55.33% among the different groups respectively. Distribution of genotype had significant difference between patients and normal control, but no significant difference was observed between self limiting infection and normal control, and between patients and self limiting infection. Comparing group of patients with group of normal control, AC genotype had more risk to hepatitis B than CC, the risk of AC was 2.412 times bigger than that of CC. We couldn’t exclude the possible correlationbetween the polymorphism of IL-10-592 and the turnover after HBV infection.
3. AA,AG and GG genotypes of IL-10-1082 locus were detected in patients and self limiting infection groups. GG genotype was not seen in normal control group. Mutant gene frequency was 3.68%,6.17% and 11.11% among the different groups respectively. Genotype distribution had significant difference among the patients and normal controls, and self limiting infection and normal control group, but no significant difference was observed among the patients and self limiting infection group. Probably there were not correlation between the polymorphism of IL-10-1082 and the turnover after HBV infection.
4. There was no correlation between the polymorphism of IL-10-592 and the level of serum transaminase, the serum virus load and the pathologic change of liver.
5. The analysis of the polymorphism of IL-10-592 and sensitivity to adefovir showed that, there probably was a correlation in the aspect of aminotransferase recovered after medication, but no correlation in the aspect of the dynamic change of DNA.
In a word, It is difficult to exclude the possible correlation between the SNPs in the promoter of IL-10 and the HBV infection. There was probably a correlation between the gene polymorphism of IL-10 and the improvement of inflammatory reaction in liver after treating with adefovir. These findings will contribute to explain the immunological mechanism of hepatitis B, and will benefit to predict individual onset risk, and to choose effective treatment at gene level.
IL-10在机体的免疫调节中起着重要作用,IL-10的分泌水平,在很大程度上取决于遗传因素,而其表达水平的改变,直接影响病毒性肝炎的易感性、严重程度、以及对治疗的敏感性等。由于IL-10启动子区的SNP能够直接影响其表达水平,因而IL-10启动子区位置的SNP是进行研究的热点。
在进行IL-10基因多态性与HBV感染的相关研究方面,国内外不同学者的研究结果不尽相同,本研究设立患者组、自限性感染组和正常对照组三组,采用病例-对照群体关联分析的方法,通过PCR-RFLP检测手段,对研究对象IL-10-592和1082位点的SNP进行检测,并进行基因分型,观察不同基因型在不同组别中的分布情况,最后运用统计学手段进行相关性分析。结果显示,IL-10-592位点在患者组、自限性感染组和正常对照组均存在AA、AC、CC 3种基因型,根据不同基因型在三组中的分布情况,不能排除IL-10-592多态性与HBV感染后转归可能存在相关性。IL-10-1082位点在患者组和自限性感染组均存在AA、AG、GG 3种基因型,正常对照组中未检测到GG基因型。根据不同基因型在三组中的分布情况,认为IL-10-1082多态性可能与HBV感染后转归无相关性。IL-10-592多态性与乙肝患者血清转氨酶水平、血清病毒载量和肝脏病理改变无相关性。IL-10-592多态性与阿德福韦酯敏感性相关分析提示,与用药后转氨酶恢复程度可能有相关性,与DNA动态变化无相关性。值得扩大样本量进一步研究。
为有关SNP的研究提供了一些新的思路。
Hepatitis B virus (HBV) infection can cause disease. The proceeding of disease and turnover show great difference. One can show with asymptomatic HBV carriers to cryptic hepatitis, acute hepatitis, chronic hepatitis, liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the interventional factors. IL-10 possesses extensive immunizing vigour. It is a immunoregulation cytokine with immunological inhibition and immunostimulation dual effects. It playes central action in body’s immunoregulation. So the change of IL-10 level, can affect susceptibility to virus hepatitis, severity and sensibility to therapy, and so on. The secretary level of IL-10 is determined by genetic factor at a large degree. IL-10 promoter takes responsibility in combination with regulatory factor for gene expression and thereby promoter SNPs can affect transcription and expression of IL-10 gene directly. SNP has hereditary stability, it has been extensively utilized as a kind of genetic marker. As for HBV infection, SNPs in promoter region of IL-10 are the hot spot of study. Not only can they affect expressed regulation of IL-10 vivo alone, but also they can control the change of IL-10 level as linked pattern, that is to shape different haplotype. So the study on gene polymorphism in promoter region of IL-10 in patients with hepatitis B has significance. This study applied case-control association analysis, aimed at identifying the correlation between gene polymorphism in IL-10promoter and turnover after HBV infection, severity of hepatitis B, and patients’sensitivity to adefovir. So can expect to clear the pathogenesy of hepatitis B and provide necessary theoretical evidence for more effective preventing and treating HBV infection.
Subjects were divided in to three groups as patients, self limiting infection and normal control. All subjects in these three groups were all Han people in the northern part of China, and they could match each other in sex and age. The SNPs of IL-10-592 and -1082 were detected and genotyping was performed using PCR-RFLP. And observing the distribution of different genotype in different groups, finally carrying out association analysis with statistically means.
The following are the major results obtained in this study.
1. The genotypic distributions of IL-10-592 and IL-10-1082 SNP in all subjects were not deviated from the H-W equilibrium (P>0.05).
2. AA,AC and CC genotypes of IL-10-592 locus were detected in patients,self limiting infection and normal control groups. Mutant gene frequency was found to be 55.56%,64.67% and 55.33% among the different groups respectively. Distribution of genotype had significant difference between patients and normal control, but no significant difference was observed between self limiting infection and normal control, and between patients and self limiting infection. Comparing group of patients with group of normal control, AC genotype had more risk to hepatitis B than CC, the risk of AC was 2.412 times bigger than that of CC. We couldn’t exclude the possible correlationbetween the polymorphism of IL-10-592 and the turnover after HBV infection.
3. AA,AG and GG genotypes of IL-10-1082 locus were detected in patients and self limiting infection groups. GG genotype was not seen in normal control group. Mutant gene frequency was 3.68%,6.17% and 11.11% among the different groups respectively. Genotype distribution had significant difference among the patients and normal controls, and self limiting infection and normal control group, but no significant difference was observed among the patients and self limiting infection group. Probably there were not correlation between the polymorphism of IL-10-1082 and the turnover after HBV infection.
4. There was no correlation between the polymorphism of IL-10-592 and the level of serum transaminase, the serum virus load and the pathologic change of liver.
5. The analysis of the polymorphism of IL-10-592 and sensitivity to adefovir showed that, there probably was a correlation in the aspect of aminotransferase recovered after medication, but no correlation in the aspect of the dynamic change of DNA.
In a word, It is difficult to exclude the possible correlation between the SNPs in the promoter of IL-10 and the HBV infection. There was probably a correlation between the gene polymorphism of IL-10 and the improvement of inflammatory reaction in liver after treating with adefovir. These findings will contribute to explain the immunological mechanism of hepatitis B, and will benefit to predict individual onset risk, and to choose effective treatment at gene level.
引文
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